National Evidence Based Guideline for Diagnosis, Prevention and ...

National Evidence Based Guideline 

for 

Diagnosis, Prevention and Management 

of Chronic Kidney Disease 

in Type 2 Diabetes 

Prepared by: 

CARI Guidelines 

Centre for Kidney Research & 

NHMRC Centre of Clinical Research Excellence 

The Children's Hospital at Westmead 

In collaboration with: 

The Diabetes Unit 

Menzies Centre for Health Policy 

The University of Sydney 

For the: 

Diabetes Australia Guideline Development Consortium 

Approved by NHMRC 

on 12 June 2009

© Commonwealth of Australia 2009 

ISBN: 978-0-9806997-2-2 (online) 

978-0-9806997-3-9 (published) 

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The Diabetes Australia Guideline Development Consortium comprises Diabetes Australia; Australian 

Diabetes Society; the Australian Diabetes Educators’ Association; the Royal Australian College of 

General Practitioners; and The Diabetes Unit, Menzies Centre for Health Policy, The University of 

Sydney. 

A link to the guideline can be found on the Diabetes Australia website: 

www.diabetesaustralia.com.au/For-Health-Professionals/Diabetes-National-Guidelines/ 

The National Health and Medical Research Council 

The National Health and Medical Research Council (NHMRC) is Australia’s leading funding body for 

health and medical research. The NHMRC also provides the government, health professionals and 

the community with expert and independent advice on a range of issues that directly affect the health 

and well being of all Australians. 

The NHMRC provided support to this project through the Guidelines Assessment Register (GAR) 

process. The GAR consultant on this project was Dr Janet Salisbury. 

The guideline was approved by the Chief Executive Officer of the NHMRC on 12 June 2009 under 

section 14A of the National Health and Medical Research Council Act 1992. Approval for the guideline 

by NHMRC is granted for a period not exceeding five years, at which date the approval expires. The 

NHMRC expects that all guidelines will be reviewed no less than once every five years. 

A link to the guideline can be found on the National Health and Medical Research Council website: 

www.nhmrc.gov.au/publications. 

Disclaimer 

This document is a general guide to appropriate practice, to be followed subject to the clinician’s 

judgement and the patient’s preference in each individual case. The guidelines are designed to 

provide information to assist decision-making and are based on the beset evidence available at the 

time of development. 

Suggested Citation 

Chadban S, Howell M, Twigg S, Thomas M, Jerums G, Alan C, Campbell D, Nicholls K, Tong A, 

Mangos G, Stack A, McIsaac R, Girgis S, Colagiuri R, Colagiuri S, Craig J. National Evidence Based 

Guideline for Diagnosis, Prevention and Management of Chronic Kidney Disease in Type 2 Diabetes. 

Diabetes Australia and the NHMRC, Canberra 2009.

Table of Contents 

Glossary of Acronyms ........................................................................................................... 1 

Kidney Disease Expert Advisory Group ................................................................................ 2 

Guideline for Prevention and Management of Chronic Kidney Disease in Type 2 Diabetes 4 

Questions for Chronic Kidney Disease .................................................................................. 5 

Summary of Recommendations and Practice Points ............................................................. 6 

Overview of Chronic Kidney Disease in Type 2 Diabetes .................................................. 10 

Introduction .......................................................................................................................... 10 

Prevalence of CKD in People with Type 2 Diabetes. .......................................................... 11 

Natural History of Chronic Kidney Disease in people with Type 2 Diabetes ..................... 12 

Type 2 Diabetes, Chronic Kidney Disease and End Stage Kidney Disease ........................ 14 

Cardiovascular Disease and Chronic Kidney Disease ......................................................... 15 

Individual Susceptibility to Type 2 Diabetes and Chronic Kidney Disease ........................ 17 

Section 1: Assessment of Kidney Function .......................................................................... 21 

Background .......................................................................................................................... 24 

Evidence ............................................................................................................................... 31 

Evidence Tables ................................................................................................................... 42 

Section 2: Prevention and/or Management of Chronic Kidney Disease ........................... 45 

Background .......................................................................................................................... 47 

Evidence ............................................................................................................................... 51 

Evidence Tables ................................................................................................................... 95 

Section 3: Cost Effectiveness and Socioeconomic Implication ........................................ 102 

Background ........................................................................................................................ 103 

Evidence ............................................................................................................................ 106 

Evidence Tables ................................................................................................................. 115 

References ............................................................................................................................. 117 

APPENDICES ...................................................................................................................... 145 

Appendix 1: Search yield table .......................................................................................... 146 

Appendix 2: Inclusion and exclusion criteria .................................................................... 149 

Appendix 3: Search strategies and terms ........................................................................... 150 

Appendix 4: NHMRC Evidence Statement Grading Forms .............................................. 155 

Appendix 5: Overview of Guideline Development Process and Methods………………167

List of Tables: 

Table 1: Classification of chronic kidney disease GFR ...................................................... 10 

Table 2 : Natural history of kidney disease in type 2 diabetes where declining GFR is 

accompanied by increasing albuminuria ............................................................... 13 

Table 3: Causes of primary kidney failure in new patients presenting to ESKD Centres in 

Table 4: 

Australia ................................................................................................................ 14 

Urine Albumin and Albumin Creatinine Ratios in Australian Aborigines and 

Europids ................................................................................................................ 18 

Table 5: Progression of microalbuminuria to overt nephropathy in people with type 2 

diabetes.................................................................................................................. 32 

Table 6: ACR – sensitivity and specificity for microalbuminuria screening ...................... 35 

Table 7: Summary of studies relevant to evidence for use of AER and ACR screening ... 37 

Table 8: GFR estimation studies with people with type 2 diabetes .................................... 40 

Table 9: 

Summary of studies relevant to the assessment of the role of glucose control in 

CKD in individuals with type 2 diabetes .............................................................. 55 

Table 10: Summary of studies relevant to the assessment of the role of blood pressure 

control and antihypertensive agents in CKD and individuals with type 2 

diabetes……………….......................................................................................... 67 

Table 11: Summary of studies relevant to the role of blood lipid profiles in CKD in 

individuals with type 2 diabetes ............................................................................ 80 

Table 12: Summary of studies relevant to the assessment of the role of dietary fat ............. 83 

Table 13: Summary of studies relevant to the assessment of the role of protein restriction . 85 

Table 14: Summary of studies relevant to the assessment of the role of restricted salt intake 

………………………………………………………………………………88 

Table 15: Summary Tables of Studies of Smoking as Risk Factor for the Development and 

Progression of CKD in People with Type 2 Diabetes ........................................... 91

Glossary of Acronyms 

ACR 

ACE 

ACEi 

AER 

ARB 

BMI 

BP 

CCB 

CG 

CHD 

CI 

CKD 

CVD 

DKD 

ESKD 

ESRD 

ESRF 

GFR 

eGFR 

GLY 

HbA1c 

HDL 

IT 

KDOQI 

LDL 

MDRD 

NEPH 

NHMRC 

OR 

QALY 

RBG 

RCT 

RIA 

RID 

RSG 

SBP 

UAC 

UAE 

UKPDS 

WHO 

Albumin creatinine ratio 

Angiotensin-converting enzyme 

Angiotensin-converting enzyme inhibitor 

Albumin excretion rate 

Angiotensin receptor blocker 

Body Mass Index 

Blood pressure 

Calcium channel blocker 

Cockcroft-Gault 

Chronic Heart Disease 

Confidence interval 

Chronic kidney disease 

Cardiovascular disease 

Diabetic kidney disease 

End stage kidney disease 

End stage renal disease 

End stage renal failure 

Glomerular filtration rate 

Estimated glomerular filtration rate 

Glyburide 

Glycated haemoglobin 

High density lipoprotein 

Immunoturbidimetry 

Kidney Disease Outcomes Quality Initiative 

Low density lipoprotein 

Modified Diet in Renal Disease 

Nephelometry 

National Health and Medical Research Council 

Odds ratio 

Quality adjusted life year 

Random blood glucose 

Randomised controlled trial 

Radioimmunoassay 

Radial immunodiffusion 

Rosiglitazone 

Systolic blood pressure 

Urinary albumin concentration 

Urinary albumin excretion 

UK Prospective Diabetes Study 

World Health Organisation 

Type 2 Diabetes Guideline 1 Chronic Kidney Disease, June 2009

Kidney Disease Expert Advisory Group 

Co-Chairs 

Professor Jonathan Craig 

Department of Nephrology 

The Children’s Hospital at Westmead 

SYDNEY NSW 

Professor Steve Chadban 

Royal Prince Alfred Hospital 

Department of Renal Medicine 

Transplantation, 

CAMPERDOWN NSW 

Australian Diabetes Society 

ADEA 

Dieticians Association of Australia 

Content Experts 

A/Professor Stephen Twigg 

Endocrinology, Discipline of Medicine 

Central Clinical School, University of Sydney 

SYDNEY NSW 

Ms Marjory Ross 

Clinical Nurse / Credentialed Diabetes Educator 

The Queen Elizabeth Hospital 

ADELAIDE SA 

Ms Annabelle Stack 

Lifestyle Disease's Stream 

Logan Hospital 

BRISBANE QLD 

A/Professor Merlin Thomas 

Danielle Alberti Memorial Centre for Diabetic 

Complications 

Baker Medical Research Institute 

MELBOURNE VIC 

A/Professor Mark Thomas 

Renal Unit 

Royal Perth Hospital 

PERTH WA 

Dr Alan Cass 

Director 

Renal and Metabolic Division 

George Institute for International Health 

SYDNEY NSW 

Professor George Jerums 

Director of Endocrinology 

Austin Health 

Heidelberg Repatriation Hospital 

WEST HEIDELBERG VIC 

Dr Kathy Nicholls 

Dept of Nephrology 

Royal Melbourne Hospital 

PARKVILLE VIC 

A/Professor George Mangos 

Department of Medicine 

St George Hospital 

KOGARAH NSW 


Dr Richard McIsaac 

Endocrine Centre of Excellence 

Austin Health & University of Melbourne 

Heidelberg Repatriation Hospital 

HEIDELBERG WEST VIC 

Consumer 

Guideline Assessment Review 

Consultant 

Medical Advisor 

Project & Research Manager 

Research Officers 

Ms Kathy Green 

NORTH RYDE NSW 2113 

Dr Janet Salisbury 

Biotext 

YARRALUMLA ACT 

Professor Stephen Colagiuri 

Institute of Obesity, Nutrition and Exercise 

Faculty of Medicine 


Dr Seham Girgis 


Australian Health Policy Institute 


Dr Martin Howell 

Research Officer 



NHMRC Centre of Clinical Research 

Excellence 

Children's Hospital at Westmead 

WESTMEAD NSW 

Allison Tong 

Research Officer 



NHMRC Centre of Clinical Research 

Excellence 

Children's Hospital at Westmead 

WESTMEAD NSW 


Guideline for Prevention and Management of Chronic 

Kidney Disease in Type 2 Diabetes 

Aim of the guideline 

This guideline covers issues related to the prevention of chronic kidney disease (CKD) in 

individuals with established type 2 diabetes. The aim is to inform and guide the management 

of individuals with type 2 diabetes with evidence based information on what interventions 

prevent the development and/or progression of CKD. The target audience of this guideline is 

health practitioners, principally general practitioners. 

These guidelines do not address the care of diabetic individuals with end-stage kidney disease 

or those who have a functional renal transplant. Such recommendations can be found 

elsewhere (www.kidney.org.au). In addition, the present guideline does not provide 

recommendations regarding the management of individuals with established CKD, with 

respect to the prevention of other (non-renal) adverse outcomes, including retinopathy, 

hypoglycaemia, bone disease and cardiovascular disease. It is important to note however, that 

in an individual with type 2 diabetes, the prevention of these complications may be a more 

important determinant for their clinical care. Consequently, each of the recommendations for 

the prevention of CKD made in these guidelines must be balanced against the overall 

management needs of each individual patient. 

Methods 

The methods used to identify and critically appraise the evidence to formulate the guideline 

recommendations are described in detail in the Overview of Guideline Development Process 

and Methods (Apendix 5). 

Guideline Format 

Questions identified by the Expert Advisory Group (EAG) for the diagnosis, prevention and 

management of CKD in type 2 diabetes are shown on the next page. 

Each of these questions is addressed in a separate section in a format presenting: 

• Recommendation(s) 

• Practice Point (s) – including experts’ consensus in absence of gradable evidence 

• Evidence Statements – supporting the recommendations 

• Background – to issues for the guideline 

• Evidence – detailing and interpreting the key findings 

• Evidence tables – summarising the evidence ratings for the articles reviewed 

For all questions combined, supporting material appears at the end of the guideline topic and 

includes: 

• References 

• Search Strategy and Yield Tables documenting the identification of the evidence sources 


Questions for Chronic Kidney Disease 

The following questions have been addressed in the preparation of the guidelines 

1. How should kidney function be assessed and how often in people with type 2 

diabetes? 

2. How should chronic kidney disease be prevented and/or managed in people with type 

2 diabetes? 

i. What is the role of blood glucose control? 

ii. What is the role of blood pressure control? 

iii. What is the role of blood lipid modification? 

iv. What is the role of diet modification? 

v. What is the role of smoking cessation? 

3. Is the prevention and management of chronic kidney disease in people with type 2 

diabetes cost effective and what are the socioeconomic implications? 


Summary of Recommendations and Practice Points 

Recommendations 

1. Kidney status in people with type 2 diabetes should be assessed by: (GRADE B)* 

a. Annual screening for albuminuria by: 

Albumin Excretion Rate (AER) – timed urine collection. 

Microalbuminuria is indicated by: 

AER 30-300 mg/24 hrs or 

AER 20-200 µg/min in timed collection 

Macroalbuminuria is indicated by: 

AER >300 mg/24 hrs or 

AER >200 µg/min in timed collection 

OR 

Albumin: Creatinine Ratio (ACR) – spot urine sample. 


ACR 2.5 - 25 mg/mmol in males 

ACR 3.5 - 35 mg/mmol in females 


ACR >25 mg/mmol in males 

ACR >35 mg/mmol in females 

If AER or ACR screening is positive for microalbuminuria: 

Perform additional ACR or AER measurements 1 to 2 times within 

3 months. Microalbuminuria is confirmed if at least 2 of 3 tests 

(including the screening test) are positive. 

If AER or ACR screening is positive for macroalbuminuria: 

Perform a 24 hour urine collection for quantitation of protein 

excretion. 

AND 

b. Annual estimation of the Glomerular Filtration Rate (eGFR). 

eGFR

2. Blood glucose control should be optimised aiming for a general HbA1c target ≤ 7%. 

(GRADE A). 

3. In people with type 2 diabetes and microalbuminuria or macroalbuminuria, ARB or 

ACEi antihypertensive should be used to protect against progression of kidney 

disease. (GRADE A) 

4. The blood pressure of people with type 2 diabetes should be maintained within the 

target range. ARB or ACEi should be considered as antihypertensive agents of first 

choice. Multi-drug therapy should be implemented as required to achieve target blood 

pressure. (GRADE A) 

5. People with type 2 diabetes should be informed that smoking increases the risk of 

chronic kidney disease (GRADE B) 


Practice Points 

• Screening for microalbuminuria and Glomerular Filtration Rate (GFR) should be 

preformed on an annual basis from the time of diagnosis of type 2 diabetes. 

• Albumin: Creatinine Ratio (ACR) should be measured using a morning urine sample, 

however random urine samples can be used. 

• Measurement of urinary albumin can be influenced by a number of factors including: 

− urinary tract infection 

− high dietary protein intake 

− congestive heart failure 

− acute febrile illness 

− menstruation or vaginal discharge 

− water loading 

− drugs (NSAIDS, ACEi) 

• Tests such as albumin concentration > 20 µg/litre or a dipstick test for albuminuria are 

semi-quantitative and should be confirmed by ACR or AER measurements. 

• GFR is most commonly estimated using the MDRD equation which is based on serum 

creatinine, age and sex. The MDRD formula tends to underestimate GFR at levels 

greater than 60 ml/min but is more accurate at lower levels. 

• GFR can be estimated using the Cockcroft-Gault formula which is based on serum 

creatinine, age, sex and body weight. The Cockcroft-Gault formula tends to 

underestimate GFR at levels less than 60 ml/min but is more accurate at higher levels. 

• Interpretation of eGFR should refer to Kidney Health Australia report, “The 

Management of chronic kidney disease (CKD) in General Practice” 

(www.kidney.org.au), in brief: 

− eGFR < 30 ml/min/1.73 m 2 indicates severe CKD (Stage 4-5) and if persistent 

should prompt referral to a nephrologist. 

− eGFR 30 to 59 ml/min/1.73 m 2 indicates moderate kidney dysfunction (Stage 

3 CKD). Referral to a nephrologist or endocrinologist interested in kidney 

disease should be considered. 

− eGFR 60-89 ml/min/1.73 m 2 may indicate mild kidney dysfunction. A 

detailed clinical assessment of glycaemic control, blood pressure and lipid 

profile is recommended in such cases. 

• The HbA1c target may need to be individualised taking in to account history of 

hypoglycaemia and co-morbidities. refer to “Blood Glucose Control in Type 2 

Diabetes” guidelines) 


• Systolic blood pressure (SBP) appears to be the best indicator of the risk of CKD in 

type 2 diabetes. However, an optimum and safest lower limit of SBP has not been 

clearly defined. 

• Due to potential renoprotective effects, the use of ACEi or ARB should be considered 

for the small subgroup of people with normal blood pressure who have type 2 

diabetes and microalbuminuria. 

• As there is limited evidence relating to effects of lipid treatment on the progression of 

CKD in people with type 2 diabetes, blood lipid profiles should be managed in 

accordance with guidelines for prevention and management of cardiovascular 

diseases. 

• Based on favourable cost studies, screening for microalbuminuria and treatment with 

antihypertensive medications should be routinely performed for the prevention and 

management of kidney disease in people with type 2 diabetes. 

• Socio-economic factors should be considered when developing programs for 

prevention, and management of CKD in people with type 2 diabetes. 


Overview of Chronic Kidney Disease in Type 2 

Diabetes 

Introduction 

Diabetes is the leading cause of Chronic Kidney Disease (CKD) in developed countries 

(Zimmet et al, 2001). The AusDiab study found 27.6% of people with diabetes had CKD and 

the prevalence of CKD was three times higher in those with diabetes compared to those 

without (AIHW 2005; Chadban et al, 2003). 

Chronic kidney disease has been defined by the Kidney Disease Outcomes Quality Initiative 

(KDOQI 2002) as: Glomerular filtration rate (GFR)

type 2 diabetes, renal and glomerular enlargement are not well documented. Proteinuria 

(macroalbuminuria) represents overt kidney disease and is defined by an AER persistently 

exceeding 200 µg/min (300 mg/24 hours). In addition it is associated with declining GFR and 

rising blood pressure. This stage usually follows several years of microalbuminuria 

(Mogensen 2003). 

Prevalence of CKD in People with Type 2 Diabetes: 

In people with type 2 diabetes, estimates of the prevalence of CKD are in the order of 5-30% 

with a cumulative incidence of approximately 10-40%. The lowest incidence is seen in 

elderly Caucasians and the highest in Pima Indians, Nauruans, Australian Aborigines, Maoris 

and African Americans. In early studies of elderly Caucasian people with type 2 diabetes, the 

risk of progression from microalbuminuria to proteinuria was reported as only 22% 

(Mogensen 1984) compared with 80% in people with type 1 diabetes and microalbuminuria 

with a similar follow up of 9 years (Mogensen & Christensen 1984). However, other studies 

in non-Caucasian people with type 2 diabetes have found a higher predictive value of 

microalbuminuria for overt nephropathy, similar to that in type 1 diabetes. For instance, in 

the Pima Indians, the four-year cumulative incidence of overt nephropathy was 37% (Nelson 

et al, 1996) and in young Jewish people with type 2 diabetes and microalbuminuria, the five 

year incidence of overt nephropathy was 42% (Ravid et al, 1993). 

Approximately 1 in 6 people with type 2 diabetes develop overt nephropathy 

(macroalbuminuria) compared with 1 in 3 people with type 1 diabetes (Tung & Levin 1988). 

Once macroalbuminuria is present, the interval to the onset of ESKD varies from 4 to 18 

years but can be delayed by intensive antihypertensive intervention based on inhibitors of the 

renin angiotensin system (Fabre et al, 1982; Parving 1998) [Refer to Section 2 of these 

guidelines]. 

In Australia, CKD associated with diabetes accounts for over 30% of new people entering 

ESKD treatment programs and has contributed to a large part of the increase in the incidence 

rate of ESKD (Australian and New Zealand Dialysis and Transplant Registry 2007). This is 

likely to continue to increase as the AusDiab study indicates that 7.4% of adult Australians 

now have diabetes, representing a 2-fold increase over the last 20 years (Barr et al, 2006; 

Dunstan et al, 2002). The ANZDATA Registry (Australian and New Zealand Dialysis and 

Transplant Registry 2007) shows a trend to an increasing proportion of new ESKD patients 

with type 2 diabetes from 28% in 2000 to 40% in 2006. In the AusDiab study the prevalence 

(adjusted for age and sex) for microalbuminuria and macroalbuminuria was 10.6% and 2.0% 

respectively in people with newly diagnosed diabetes and 23.2% and 5.8% respectively for 

those with known diabetes (Tapp et al, 2004). Furthermore, the prevalence of albuminuria 

increased with increasing glycaemia. People with diabetes and impaired glucose tolerance 

had an increased risk for albuminuria compared to those with normal glucose tolerance, 

independent of other known risk factors for albuminuria (including age and sex). 

Despite survival bias, whereby many people with kidney disease and type 2 diabetes do not 

reach ESKD because of the increased cardiovascular mortality, CKD in people with type 2 

diabetes is still the single most common cause of ESKD in Europe (Ritz & Orth 1999) and in 

the United States where it accounts for approximately 50% of all people enrolled in ESKD 

programs (US Renal Data System 2007). The review by Stewart and colleagues concluded 

that the increasing trend in the incidence of type 2 diabetes was a prime cause of the 

increasing incidence of ESKD in Australia (Stewart et al, 2004). 


Natural History of Chronic Kidney Disease in people with Type 2 Diabetes 

The natural history of CKD in people with type 2 diabetes has been characterised by changes 

in AER which may progress through three phases namely: normoalbuminuria (AER 200 µg/min) [Table 2]. The proportion of people with type 2 diabetes who develop 

microalbuminuria is in the order of 25% after 10 years (Mogensen 2003). The stage of 

proteinuria, also called overt nephropathy, is typically characterised by the onset of a decline 

in GFR, and subsequently a rise in serum creatinine. Increased serum creatinine above the 

normal range occurs relatively late and indicates a loss of at least 50% of total kidney 

function. It should be noted that kidney disease remains asymptomatic until about 75% of 

kidney function has been lost (Bakris et al, 2000). However, up to 30% of people with type 2 

diabetes who have a GFR < 60 ml/min/1.73 m 2 (i.e. Stage 3 CKD) may remain 

normoalbuminuric (Bash et al, 2008; Kramer & Molitch 2005). For this group the natural 

history of kidney disease has yet to be defined. 

The GFR in people with type 2 diabetes typically begins to decline in the late 

microalbuminuric stage and, without intervention declines at an average rate of 8- 

12 ml/min/1.73 m 2 /year (Biesenbach et al, 1994). However, it is important to note, that up to 

30% of people with type 2 diabetes may be normoalbuminuric and have a GFR

Table 2 : Natural history of kidney disease in type 2 diabetes where declining GFR 

is accompanied by increasing albuminuria 

Stage Urinary albumin Dipstick GFR* 

AER 

ACR 

(ml/min per 

1.73 m 2 ) 

Normal 

Incipient kidney 

disease 

(Microalbuminuria) 

Overt nephropathy 

(Proteinuria / 

Macroalbuminuria) 

< 20 µg/min 

< 30 mg/24h 

20-200 µg/min 

30-300 mg/24h 

≥ 200 µg/min 

> 300 mg/24h 

< 2.5 mg/mmol 

male 

< 3.5 mg/mmol 

female 

2.5-25 mg/mmol 

male 

3.5-35 mg/mmol 

female 

≥ 25 mg/mmol male 

≥ 35 mg/mmol 

female 

Negative Normal or 

increased 

≥90 

Negative 

Positive 

Normal or 

onset of 

decreased 

60-89 

Decreased 

30-59 

Renal insufficiency As above As above Positive Decreased 

15-29 

ESKD As above As above Positive Decreases 

eflect different patterns of renal ultrastructural change including typical lesions, 

nephrosclerosis or forms of glomerular disease of non-diabetic type (Gambaro et al, 1993; 

Parving et al, 1992). Biopsy studies in people with type 2 diabetes have found non-diabetic 

lesions were present in about 10% to 30% of people with type 2 diabetes who had overt 

kidney disease but did not have retinopathy (Goldstein & Massry 1978; Olsen & Mogensen 

1996; Schwartz et al, 1998). In approximately 25% of biopsies from people with diabetes and 

macroalbuminuria, coexistent non-diabetic kidney disease has been found (Parving et al, 

1992; Taft et al, 1990). In a study of 53 randomly selected people with type 2 diabetes and 

microalbuminuria, no cases of definable non-diabetic kidney disease were found (Fioretto et 

al, 1998; Goldstein & Massry 1978). Furthermore, the rate of kidney disease progression may 

not be clearly related to the type of underlying glomerular ultrastructural lesions but rather to 

the level of urinary protein excretion (Ruggenenti et al, 1998). Thus, kidney biopsy is 

generally not warranted to establish a diagnosis of diabetic nephropathy. 

Type 2 Diabetes, Chronic Kidney Disease and End Stage Kidney 

Disease 

A worldwide increase in type 2 diabetes is contributing to an epidemic of diabetic related 

ESKD. Kidney disease in people with type 2 diabetes has been the most common cause of 

ESKD in Australia since 2004 (Table 3) (Australian and New Zealand Dialysis and 

Transplant Registry 2007). People from disadvantaged and transitional populations are 

disproportionately affected. Factors contributing to the high incidence rates of ESKD in 

these groups include a complex interplay between genetic susceptibility, age of onset of 

diabetes, glycaemic control, elevated blood pressure, obesity, smoking, socio-economic 

factors and access to health care [refer to Section 3 of these guidelines]. 

Table 3: Causes of primary kidney failure in new patients presenting to ESKD 

Centres in Australia 

Cause of ESKD 

% ESKD Patients 

2003 2004 2005 2006 

Diabetic Nephropathy 26 30 31 32 

Glomerulonephritis 27 25 24 23 

Hypertension 15 13 15 15 

Polycystic Kidney Disease 5 7 7 6 

Analgesic Nephropathy 4 2 3 2 

Reflux Nephropathy 4 3 3 4 

Miscellaneous 12 13 11 13 

Uncertain Diagnosis 7 7 6 5 

Source: ANZDATA Registry Report 2007 

Chronic kidney disease affects approximately 5-30% of people with type 2 diabetes. At the 

time of diagnosis, an average of 15% of people with type 2 diabetes across all ethnic groups 

have elevated urinary albumin excretion. Progression to ESKD occurs in only 5-10% of 

elderly Caucasian people with type 2 diabetes, however this figure may be much higher in 

other populations (DeFronzo & Goodman 1995). ESKD is increasing in Australia in part 

related to the increase in type 2 diabetes in younger people (Dunstan et al, 2002). In 

Australia during 2006, diabetes was the primary cause of kidney disease in 32% of new 

patients presenting to ESKD centres followed by glomerulonephritis (23%) (Australian and 

New Zealand Dialysis and Transplant Registry 2007). The multinational review of End Stage 


Renal Disease (ESRD) registries by the (ESRD Incidence Study Group et al, 2006) indicates 

an overall reduction in non diabetic causes of ESRD which the group consider to be 

consistent with the success of secondary prevention measures. However the study group 

have estimated that diabetic ESRD (which is predominantly type 2 diabetes) has “continued 

to increase by over 3% per year in persons aged 45-64 years in the Europid populations in 

the study.” The estimate was made after accounting for changes in access to renal 

replacement therapy with time. 

Diabetes is the leading cause of ESKD in Indigenous Australians accounting for 

approximately 48% of cases compared to approximately 23% in non Indigenous Australians 

over the period 2003 to 2006 (Appendix II of the ANZDATA Registry Report 2007). Studies 

over the last ten years have documented that in Aboriginal Australians, renal deaths have 

increased from 18 to 30-fold and the incidence of ESKD approaches 1000/million (Spencer et 

al, 1998). In the Northern Territory of Australia, all cause ESKD is 21 times higher in 

Aboriginal and Torres Strait Islanders communities compared with non-Aboriginal 

Australians. In addition, the incidence of ESKD is doubling every 3-4 years, in part because 

of better detection but also in real terms. In the Northern Territory, 96% of people on dialysis 

are Aboriginal and Torres Strait Islanders although they represent only 28% of the population 

(Spencer et al, 1998). Even within the Aboriginal population there is much heterogeneity, 

with the incidence of ESKD being 5-fold greater in the Tiwi Community than in the East 

Arnhem Community. Although multiple factors have been implicated, including poststreptococcal 

glomerulonephritis, an increased prevalence of diabetes is an important 

contributing factor. More recently Preston-Thomas et al (2007) confirmed the high rates of 

ESKD amongst Indigenous Australians, with the highest rates (17 times higher than the total 

Australian population) occurring in the most remote regions. The rate of increase in ESKD 

may be slowing which in turn may be consistent with a slowing in the rise in mortality rates 

in some chronic diseases in Indigenous Australians, however, not enough is known about the 

extent of early CKD (a predictor of CVD mortality and ESKD) in Indigenous Australians 

(Preston-Thomas et al, 2007). 

In people with type 2 diabetes, progression of microalbuminuria to proteinuria varies with 

ethnicity and age, but once proteinuria is present the course of kidney disease is similar. 

Microalbuminuria affects an average of 25 to 30% of people with type 2 diabetes (Klein et al, 

1993; Mattock et al, 1992). Although the prevalence of microalbuminuria is similar in type 1 

and type 2 diabetes (Gall et al, 1991), the cumulative risk of ESKD is less in people with type 

2 diabetes compared with type 1 diabetes, with one early study showing a cumulative risk of 

ESKD of 11% (Humphrey et al, 1989). The main reason for this disparity is that most 

Caucasian people with type 2 diabetes die from CVD before developing overt diabetic kidney 

disease (Schmitz & Vaeth 1988) resulting in survivor bias in published studies. 

Cardiovascular Disease and Chronic Kidney Disease 

Microalbuminuria is an independent risk factor for cardiovascular diseases (CVD) (Beilin et 

al, 1996; Dinneen & Gerstein 1997; Gerstein et al, 2001; Mogensen 2003). The presence of 

microalbuminuria in people with type 2 diabetes and elevated blood pressure indicates a 2-4 

fold increase in cardiovascular risk when compared with those who are normoalbuminuric 

matched for age, sex and duration of diabetes (Mattock et al, 1992; Mogensen 1984; Schmitz 

& Vaeth 1988). This link between AER and CVD risk is considered by some to extend into 

what is currently defined as the normoalbuminuric range (Ritz 2006). However, it is still 

uncertain whether an increase in AER into the microalbuminuric range is itself contributing 

to the pathogenesis of vascular disease (Mogensen 1999). This is because microalbuminuria 

is usually associated with known cardiovascular risk factors, including raised blood pressure, 

quantitative and qualitative changes in the lipid profile, and procoagulant changes in the 

coagulation sequence. Ritz (2006) notes that there is growing evidence for a link between the 


progression of albuminuria and development of insulin resistance in type 2 diabetes and that 

kidney disease may need to be considered as a key component rather than a consequence of 

the metabolic syndrome. However, there is insufficient evidence to test the hypothesis that 

minor derangements of kidney function directly cause endothelium dysfunction and thus 

directly contribute to CVD (Ritz 2006). 

Risk factors shared by people with type 2 diabetes and CVD account for the excessive 

morbidity and mortality caused by macrovascular disease (Laakso 1998). Increased urinary 

albumin is more closely associated with CVD than ESKD in people with type 2 diabetes 

(Deckert et al, 1992; Mogensen 1984). 

Microalbuminuria is a strong predictor of total and CVD mortality and morbidity in people 

with type 2 diabetes (Dinneen & Gerstein 1997). Kidney disease significantly increases 

cardiovascular morbidity and mortality in people with type 2 diabetes, being 2-4 fold higher 

in the presence of microalbuminuria and 4-8 fold higher with overt kidney disease (Gerstein 

et al, 2001). In the United Kingdom Prospective Diabetes Study (UKPDS) study, the death 

rate of individuals with type 2 diabetes with macroalbuminuria was greater than the rate of 

progression of ESKD (Adler et al, 2003). Microalbuminuria has also been associated with a 

three fold increase in the risk of hospitalisation for heart failure (Schocken et al, 2008). 

Apart from its links with diabetic kidney disease, microalbuminuria also reflects widespread 

vascular disease (Deckert et al, 1992). Microalbuminuria independently predicts total and 

cardiovascular mortality in people with type 2 diabetes (Beilin et al, 1996; Jarrett et al, 1984; 

Mattock et al, 1992; Mogensen 1984) as well as in non-diabetic subjects (Damsgaard et al, 

1990; Yudkin et al, 1988). In some but not all of these studies microalbuminuria predicted 

mortality independently of other conventional cardiovascular risk factors such as 

dyslipidaemia, elevated blood pressure and smoking. 

People with type 2 diabetes and microalbuminuria have an annual total mortality of 8% and a 

cardiovascular mortality of 4% which is up to 4-fold higher than in people with type 2 

diabetes without microalbuminuria (Mattock et al, 1992; Mogensen 1984; Schmitz & Vaeth 

1988). Several longitudinal studies in Caucasian people with type 2 diabetes have confirmed 

that microalbuminuria is a better predictor of cardiovascular events than of microvascular 

disease (Gall et al, 1991; Mattock et al, 1992; Schmitz & Vaeth 1988). In elderly people with 

type 2 diabetes, the 10 year mortality is approximately 2-4 times higher in microalbuminuric 

compared with normoalbuminuric people (Mogensen 1984). 

The exact molecular mechanisms linking an increase in urinary albumin to CVD are not 

known. However, increased AER is associated with generalised endothelial dysfunction 

(Deckert et al, 1992) which results in increased capillary permeability, a shift towards a 

procoagulant state and reversal of the normal vasodilatory response to acetylcholine. To what 

degree this increase in vascular risk is mediated by conventional risk factors such as elevated 

blood pressure, dyslipidaemia and glycaemic control as opposed to a specific effect of 

increased AER remains unclear. 

Many factors may contribute to the increase in cardiovascular events associated with 

microalbuminuria. These include poor metabolic control which is also a risk factor for the 

progression of microalbuminuria in type 2 diabetes (Fioretto et al, 1996; Schmitz & Vaeth 

1988) and high blood pressure (Tanaka et al, 1998). Other macrovascular risk factors include 

dyslipidaemia and hyperinsulinaemia (Niskanen et al, 1990; Uusitupa et al, 1993), indices of 

endothelial dysfunction including increased levels of Von Willebrand factor (Stehouwer et al, 

1992), increased platelet adhesiveness and increased PAI-I and fibrinogen levels (Deckert et 

al, 1992; Nagi et al, 1996). Microalbuminuria in type 2 diabetes is also associated with 


dyslipidaemia which has worsened in parallel with progression of proteinuria (Jerums et al, 

1993). 

Whilst there is uncertainty with respect to the relationship between CKD and the 

pathogenesis of CVD, it is clear that the prevention and management of CKD in people with 

type 2 diabetes is key to reducing their risk of CVD. 

Individual Susceptibility to Type 2 Diabetes and Chronic Kidney 

Disease 

There are racial, social, dietary and physical differences in susceptibility to type 2 diabetes 

and in rates of progression to its complications. In the United States, diabetic microvascular 

disease is substantially more common in minority populations. In people with type 2 diabetes 

proteinuria is twice as common in Mexican Americans than in non-Hispanic whites (Haffner 

et al, 1989). The rate of ESKD is up to 4 times higher in African Americans (Cowie et al, 

1989), and more than 10 times higher in native Americans (Stahn et al, 1993) than in whites. 

The observational study by Karter et al (2002) of in excess of 62,000 people with diabetes 

with comparable health insurance coverage in the US indicate ethnic disparities for a range of 

complications despite similar access to medical services. The age and sex adjusted incidence 

of ESKD was highest for African-Americans at 6.8 per 1000 person years and lowest for 

Caucasians at 3.2 per 1000 person years. The ethnic differences were not consistent across 

the five health outcomes assessed with incidence rates for myocardial infarction, stroke, 

congestive heart failure and lower extremity amputation being similar. 

Studies from a number of countries have shown that the prevalence of kidney disease in 

people with type 2 diabetes is high in certain ethnic groups. Diabetic nephropathy is a 

common primary cause of ESKD in New Zealand Maoris and in Pacific Islanders accounting 

for 61% and 49% of cases, respectively (Ritz & Orth 1999). These higher rates of ESKD also 

apply to Mexican Americans, African Americans and Indian Subcontinent (Burden et al, 

1992; Held et al, 1991; Pugh et al, 1995). On the other hand data from the U.S. Renal Data 

System show that African Americans survive longer than Caucasians on dialysis (Held et al, 

1991). 

The prevalence of microalbuminuria and proteinuria is higher in Asians, Indians, African 

Americans and Hispanics compared with Caucasians. In many of these studies, these 

differences persist after correction for blood pressure, duration of diabetes and metabolic 

control (Allawi et al, 1988; Garza et al, 1997; McGill et al, 1996; Savage et al, 1995; Weijers 

et al, 1997). 

An Australian study compared differences in the prevalence of microalbuminuria and 

proteinuria and elevated blood pressure among 1845 consecutive people with type 2 diabetes 

attending a Diabetes Centre for complications assessment (McGill et al, 1996). The seven 

ethnic groups in the study were Anglo-Celtic (n=896), Italian (n=246), Greek (n=209), 

Arabic (n=147), Chinese (n=131), Indian (n=115) and Aboriginal (n=101). After correction 

for age, duration of diabetes and glycaemic control, the Odds Ratio for microalbuminuria 

[based on 1 timed AER of 50-200 µg/min] relative to Anglo-Celts were higher in all groups 

and reached statistical significance for Arabic (OR 2.1; p

susceptibility to CKD. Another possibility is that the rate of progression of diabetic kidney 

disease differs between ethnic groups, however, there are conflicting data on this issue (Garza 

et al, 1997; Koppiker et al, 1998; Varughese & Lip 2005). The review by Lindner et al 

(2003) concludes that overall the available studies indicate that diabetic nephropathy has a 

strong dependence on ethnicity with Caucasians of European origin having the lowest 

prevalence compared to North American Indigenous groups and African Americans. 

Differences in the expression of kidney disease in different populations are related in part to 

marked differences in the age of onset of type 2 diabetes. There is a higher prevalence and 

more rapid progression of kidney disease in younger, non-Caucasian people with type 2 

diabetes than in older Caucasian people with type 2 diabetes. The exact reasons for this are 

unknown. In Caucasian populations the onset of type 2 diabetes is usually between the sixth 

and ninth decades and kidney disease is confounded by the co-existence of elevated blood 

pressure and renal atherosclerosis. By contrast, in populations such as the Pima Indians and 

Aboriginal Australians, the onset of type 2 diabetes is generally between the third and sixth 

decades (Nelson et al, 1993; O'Dea 1991). The ANZDATA 2007 annual report (Australian 

and New Zealand Dialysis and Transplant Registry 2007) shows a disparity occurring in the 

relative incidence of ESKD between Aboriginal and non-Aboriginal Australians (peak 

incidence ratio approximately 15) in the 40 to 59 age group. Ethnic differences in the natural 

history of CKD in type 2 diabetes likely reflects a complex interplay between genetic 

predisposition to kidney disease and associations with vascular risk factors such as elevated 

blood pressure, dyslipidaemia and smoking (e.g. Satko et al, 2007). In addition, 

socioeconomic deprivation, with its attendant effects on access and attitudes to medical care, 

may play a role [refer to Section 3 of these guidelines]. The effects of the ageing process on 

kidney function may also play a part in differentiating kidney disease in type 2 diabetes from 

that in type 1 diabetes. 

In Aboriginal Australians with type 2 diabetes, the nature of kidney disease is more complex 

than in other populations and it is not clear what proportion of kidney disease is attributable 

to diabetes. The presence of skin infections, post-streptococcal glomerulonephritis, 

alcoholism, multiparity in women and a family history of kidney disease, as well as features 

of the metabolic syndrome, are all associated with an increase in urinary albumin (Hoy 2000). 

A population-based cross-sectional study in south-eastern Australia (Guest et al, 1993) 

highlighted the increased prevalence of albuminuria in Aboriginal Australians compared with 

Europids (Australians of European descent) (Table 4). 

Table 4: Urine Albumin and Albumin Creatinine Ratios in Australian Aborigines 

and Europids 

Albumin 

concentration 

>0.03 g/L 

Albumin:creatinine 

ratio 

≥ 1.30 mg/mmol 

Source: Guest et al (1993) 

Aboriginal 

men 

n=31 

Europid 

men 

n=148 

Aboriginal 

women 

n=62 

Europid 

women 

n=154 

36% 14% p

significantly higher prevalence of macroalbuminuria (1 measurement: >200 µg/min) in 

Aboriginal people compared with Anglo-Celtic people (OR 3.1; p

Summary – Characteristics of Chronic Kidney Disease in Type 2 

diabetes 

• CKD in people with type 2 diabetes is the most common cause of ESKD in Australia. 

This largely reflects the increasing prevalence of type 2 diabetes in the Australian 

population. 

• CKD in people with type 2 diabetes is a major risk factor for cardiovascular and all cause 

mortality. 

• The majority but not all of CKD in type 2 diabetes is caused by diabetic kidney disease, 

and a definitive diagnosis (e.g. by biopsy) is likely to be of little value in overall patient 

management compared to assessment of albuminuria and rate of decline in GFR. Stages 

of CKD and subsequent recommendations for management have been defined on this 

basis. 

• CKD in people with type 2 diabetes classically falls into two stages: incipient 

nephropathy (microalbuminuria with normal or elevated GFR) and overt nephropathy 

(macroalbuminuria, proteinuria and declining GFR) with the natural history of 

progression being from normal to incipient to overt nephropathy to ESKD. However, in 

people with type 2 diabetes who develop GFRs of < 60 ml/min/1.73m2 up to 30% have 

no significant albuminuria and for this group the natural history is yet to be defined. 

• There is a strong association between CKD and CVD in people with type 2 diabetes. 

• Familial clustering and ethnic differences in the prevalence of CKD in type 2 diabetes as 

well as genetic studies indicate a heritable component. However, this is likely to involve 

a complex interaction between environment and genetic susceptibility to factors 

associated with the natural history of CKD in type 2 diabetes, such as elevated blood 

pressure and hyperglycaemia as well as genetic factors related to renal outcomes. 


Section 1: Assessment of Kidney Function 

Question 

How should kidney function be assessed and how often in people with type 2 diabetes? 


Kidney status in people with type 2 diabetes should be assessed by: (GRADE B)* 

a. Annual screening for albuminuria by: 

Albumin Excretion Rate (AER) – timed urine collection. 


AER 30-300 mg/24 hrs or 

AER 20-200 µg/min in timed collection 


AER >300 mg/24 hrs or 

AER >200 µg/min in timed collection 

OR 

Albumin: Creatinine Ratio (ACR) – spot urine sample. 


ACR 2.5 - 25 mg/mmol in males 

ACR 3.5 - 35 mg/mmol in females 


ACR >25 mg/mmol in males 

ACR >35 mg/mmol in females 

If AER or ACR screening is positive for microalbuminuria: 

Perform additional ACR or AER measurements 1 to 2 times 

within 3 months. Microalbuminuria is confirmed if at least 2 of 3 

tests (including the screening test) are positive. 

If AER or ACR screening is positive for macroalbuminuria: 

Perform a 24 hour urine collection for quantitation of protein 

excretion. 

AND 

b. Annual estimation of the Glomerular Filtration Rate (eGFR). 

eGFR


• Screening for microalbuminuria and Glomerular Filtration Rate (GFR) should be 

preformed on an annual basis from the time of diagnosis of type 2 diabetes. 

• Albumin: Creatinine Ratio (ACR) should be measured using a morning urine 

sample, however random urine samples can be used. 

• Measurement of urinary albumin can be influenced by a number of factors 

including: 

- urinary tract infection 

- high dietary protein intake 

- congestive heart failure 

- acute febrile illness 

- menstruation or vaginal discharge 

- water loading 

- drugs (NSAIDS, ACEi) 

• Tests such as albumin concentration > 20 µg/litre or a dipstick test for albuminuria 

are semi-quantitative and should be confirmed by ACR or AER measurements. 

• GFR is most commonly estimated using the MDRD equation which is based on 

serum creatinine, age and sex. The MDRD formula tends to underestimate GFR at 

levels greater than 60 ml/min but is more accurate at lower levels. 

• GFR can be estimated using the Cockcroft-Gault formula which is based on serum 

creatinine, age, sex and body weight. The Cockcroft-Gault formula tends to 

underestimate GFR at levels less than 60 ml/min but is more accurate at higher 

levels. 

• Interpretation of eGFR should refer to Kidney Health Australia report, “The 

Management of chronic kidney disease (CKD) in General Practice” 

(www.kidney.org.au), in brief: 

- eGFR < 30 ml/min/1.73 m 2 indicates severe CKD (Stage 4-5) and if 

persistent should prompt referral to a nephrologist. 

- eGFR 30 to 59 ml/min/1.73 m 2 indicates moderate kidney dysfunction 

(Stage 3 CKD). Referral to a nephrologist or endocrinologist interested in 

kidney disease should be considered. 

- eGFR 60-89 ml/min/1.73 m 2 may indicate mild kidney dysfunction. A 

detailed clinical assessment of glycaemic control, blood pressure and lipid 

profile is recommended in such cases. 


Evidence Statements 

• Microalbuminuria is a key predictor for the development of CKD in people with type 2 

diabetes, however CKD may develop in the absence of abnormalities in albumin 

excretion 

Evidence Level II - Prognosis 

• AER and ACR are the most common and reliable methods to assess albuminuria based 

on sensitivity and specificity, however both methods are subject to high intra-individual 

variability so that repeat tests are needed to confirm the diagnosis 

Evidence Level III - Diagnostic Accuracy 

• Estimation of GFR (eGFR) based on serum creatinine is a pragmatic, clinically relevant 

approach to assessing kidney function in people with type 2 diabetes 

Evidence Level III - Diagnostic Accuracy 


Background – Assessment of Kidney Function in Type 2 

Diabetes 

Introduction 

It is important to recognise that CKD in individuals with type 2 diabetes is a multifactorial 

disorder, to which diabetes, elevated blood pressure, atherosclerosis, endothelial dysfunction 

and many other factors potentially contribute. In routine clinical practice and in most clinical 

trials it is not possible to determine the aetiology of CKD in individuals with type 2 diabetes. 

For example, the prevention of microalbuminuria in a type 2 diabetes trial may be due to 

effects on diabetic kidney disease, hypertensive kidney disease, or endothelial function. 

However, this question is irrelevant in diabetes care, as the presence of CKD is associated 

with adverse outcomes irrespective of the aetiology. 

The introductory section of these guidelines provides a overview of the characteristics and 

progression of kidney disease in people with type 2 diabetes that form the basis for 

consideration of the assessment of kidney function. Screening for CKD aims to identify 

abnormal urine albumin excretion and declining GFR, so that interventions can be given to 

slow progression of kidney disease, to prevent ESKD and to reduce the risk of a CVD. 

Assessment of kidney function in people with type 2 diabetes includes measurement of 

urinary albumin excretion and estimation of GFR for the following purposes: 

• Screening 

• Diagnosis 

• Monitoring response to management 

In a significant proportion of people with type 2 diabetes, CKD may progress (i.e. declining 

GFR) in the absence of increasing albuminuria. Thus both GFR and albuminuria are 

important in screening, diagnosis and monitoring. Albuminuria may be assessed by 

measurement of the Albumin Excretion Rate (AER) or the Albumin Creatinine Ratio (ACR) 

with AER being regarded as the gold standard. The GFR is most commonly estimated rather 

than measured. 

Albumin excretion typically increases in a continuous manner over several years, rather than 

showing an abrupt transition from normal to abnormal values. The average increase in AER 

ranges from 10-30% per year until overt nephropathy develops. However, in some people, the 

rate of increase in AER slows after the stage of microalbuminuria (Mogensen 2003). 

Regression from microalbuminuria to normoalbuminuria may occur in people with newly 

diagnosed type 2 diabetes due to interventions or for unknown reasons (KDOQI 2007; 

McIntosh et al, 2002), whilst in others regression does not occur (Niskanen et al, 1993). 

Regular monitoring of albuminuria in people with type 2 diabetes is warranted on the basis of 

the rate of progression of albuminuria in type 2 diabetes and ESKD associated with 

increasing albuminuria and the increased risk of CVD (Adler et al, 2003). 

There is a high intra-individual variability in 24h albumin excretion with a coefficient of 

variation of 40-50%, therefore a diagnosis of persistent microalbuminuria should be based on 

repeated measurements, especially if long-term treatment of normotensive individuals are 

being considered. 

Whilst increasing albuminuria is a risk factor for both CVD and ESKD, cross sectional 

studies have also shown a higher degree of heterogeneity in people with type 2 diabetes 

compared to type 1 diabetes with respect to CKD. As such a significant proportion of people 

with type 2 diabetes may have CKD and be normoalbuminuric (Kramer & Molitch 2005; 


McIntosh et al, 2002; Tapp et al, 2004). In the recently reported ARIC study [a population 

based prospective biracial long term observational study of 2,187 individuals with 

predominantly type 2 diabetes], 30% of incident CKD (defined as eGFR < 60 ml/min/1.73m 2 

or kidney disease at hospitalisation) did not have albuminuria (ACR ≥ 30 mg/g) (Bash et al, 

2008). 

In people who do not have diabetes, the expected rate of decline in GFR with ageing is 

approximately 1 ml/min per year (Kesteloot & Joossens 1996). A proportion of people with 

type 2 diabetes show a more rapid decline in GFR, in the absence of microalbuminuria or 

macroalbuminuria (Tsalamandris et al, 1994). In people with type 2 diabetes and established 

nephropathy, longitudinal studies have documented a decline in GFR without intervention of 

about 10 ml/min/year (Biesenbach et al, 1994). In people with type 1 diabetes, and overt 

kidney disease, the extent of early reduction in AER by ACEi predicts the degree of 

protection from subsequent decline in GFR) (Rossing et al, 1994). Whether this occurs in 

people with type 2 diabetes is not yet known. 

Cross-sectional studies in people with type 2 diabetes and microalbuminuria have generally 

shown that GFR is normal, however, increased GFR (hyperfiltration) have been observed in 

cross sectional studies. For example the cross-sectional study of 158 microalbuminuric 

Danish patients where the GFR was increased (139 ± 29 ml/min) compared with 39 patients 

with normoalbuminuria (115 ± 19 ml/min) and 20 control subjects without diabetes (111 ± 23 

ml/min) (Vedel et al, 1996). However, the cross-sectional study by Premaratne et al (2005) 

of 662 Australian people with type 2 diabetes showed no significant difference in AER and 

prevalence of microalbuminuria between hyperfilters and normofilters. 

In people with type 2 diabetes and microalbuminuria some but not all longitudinal studies 

have documented a decline in GFR without intervention of about 3-6 ml/min/year. Lack of 

uniformity in results is in part due to study design, since most studies have focussed on 

albuminuria and have been too short to document clinically significant changes in GFR. In a 

Japanese study over 48 months, no change in GFR was demonstrated in 48 patients who were 

either untreated or treated with nifedipine, enalapril or both drugs (Sano et al, 1994). In 

another study of 103 normotensive Indians over 5 years, there was no change in GFR during 

treatment with placebo or enalapril (Ahmad et al, 1997). 

By contrast, two studies have shown a significant decline in GFR in at least one study arm. In 

a 5 year study of 94 middle aged normotensive Israelis, GFR remained stable in those treated 

with enalapril but declined in those treated with placebo (Ravid et al, 1993). This study used 

the inverse of the serum creatinine level as an index of GFR. In a 3 year study of 18 

hypertensive Italians, the GFR (measured isotopicaly) decreased in those treated with 

cilazapril or amlodipine (Velussi et al, 1996). In three other long term studies of 

microalbuminuric patients kidney function there was no change in serum creatinine over 5 

years in a study of 102 hypertensive patients from Hong Kong (Chan et al, 2000) in a 3 year 

study of 10 hypertensive Italian patients (Gambardella et al, 1991) and in a 3 year study of 

normotensive and hypertensive French patients (Lacourciere et al, 1993). 

Although not recognised as a stage of CKD, hyperfiltration (GFR > 130 ml/min/1.73 m2) 

represents an early phase of kidney dysfunction in diabetes. However, its clinical 

significance remains controversial. By definition, this phase can only be detected by 

measurement of GFR. 


Laboratory Methods 

The methods which can be used to assess urinary albumin and protein excretion include: 

• Dipstick 

• Measurement of AER on timed urine samples 

• Measurement of ACR on spot urine 

Timed urine collection, either 24h or overnight (usually 8h) is considered the gold standard 

for the measurement of albuminuria e.g (Polkinghorne, 2006). Shorter timed collection 

periods can be used (e.g. 4h) but these are time consuming for both patients and staff. AER 

and ACR on early morning urine are preferred as these tests are not subject to concentration 

bias. 

Considerations in choosing a particular test for assessment of albuminuria include: 

• The purpose for which the test is being done 

• The performance of the assay 

• The convenience and practicalities of specimen collection 

Screening will result in identification of individuals who have an increased risk of kidney and 

cardiovascular morbidity and mortality. Screening should not be reserved for known high risk 

populations (e.g. age >40 years, Australian Aborigines, positive family history of kidney 

disease) but should be offered to all people with type 2 diabetes. In people with 

microalbuminuria, a reduction in AER has been documented with improved glycaemic 

control, blood pressure control, lipid profile optimization and specific renoprotective therapy 

with ACEi, or ARB (Mogensen 2003). 

The evidence for how kidney function should be assessed consists mainly of cross sectional 

studies assessing various diagnostic tests against a reference method. In various clinical 

situations, ACR has been proposed as both a screening and diagnostic test for kidney disease 

(Connell et al, 1994). However many have recommended the use of ACR only in screening 

(Bennett et al, 1995; Jerums et al, 1994; Mogensen 1995; Viberti et al, 1994), as the test has a 

high false positive rate and low specificity. Albumin-to-creatinine ratio is also considered to 

have a useful monitoring role in diabetes with respect to detecting kidney disease progression 

and the evaluation of treatment effects (Warram et al, 1996). 

All of the original assessments of microalbuminuria were based on AER measurements in 

timed urine collections. AER measurements performed in this way are still regarded as the 

gold standard for assessment of microalbuminuria. This presumes that the assay technique is 

sufficiently sensitive, the interassay coefficient of variation is less than 15% and at least 2 of 

3 urine samples are in the appropriate range before a diagnosis of microalbuminuria is made 

(Sacks et al, 2002). 

Albuminuria is commonly measured in the clinical laboratory by one of the following 

methods: radioimmunoassay (RIA), nephelometry (NEPH), immunoturbidimetry (IT) or 

radial immunodiffusion (RID). All of these methods are available as commercial kits. RIA is 

considered as the reference method for albumin measurement as it is the longest established 

assay. In an evaluation of RID, IT, NEPH against RIA the intra and interassay coefficient of 

variation (CV) of the methods were not found to be significantly different (Tiu et al, 1993). A 

second study has also found similar degrees of precision and accuracy between the RIA, RID, 

and IT methods. The IT method was found to be consistently lower than the RIA method (the 

difference was greatest for albumin concentrations > 30mg/L) although the difference was 

considered to be not clinically important (Watts et al, 1986). Comparison of albumin 


concentrations measured by the different methods has however shown greater variability (Tiu 

et al, 1993; Watts et al, 1986). 

Size-exclusion High-Performance Liquid Chromatography (HPLC) has been shown to give 

consistently higher urinary albumin concentrations particularly in people with diabetes when 

compared to the routine immunoassay techniques (Comper, 2004; Comper, 2005; Osicka, 

2004; Russo, 2007).. The difference has been attributed to the presence of 

immunochemically nonreactive albumin which if measured has been postulated to allow for 

earlier prediction of microalbuminuria in people with type 1 and type 2 diabetes (Osicka, 

2004). However, whether HPLC detects a form of albumin not detected by immunoassay 

(i.e. non-immunoreactive) or other molecules of approximately the same size as albumin, 

remains unresolved (Miller, 2009). An analysis of the AusDiab cohort, identified both HPLCdetected 

albumin and albumin detected by immunonephelometry as risk factors for mortality, 

however HPLC detected albumin identifies some people at increased risk of mortality that are 

not detected by immunonephelometry (Magliano, 2007). The clinical significance of HPLC 

versus immunoassay detected urinary protein has not been established (Polkinghorne, 2006). 

The choice of method to be used by a particular laboratory depends on factors such as 

equipment availability, the number of samples to be processed and the required turnover time 

for results. There are advantages and disadvantages for each of the methods and these are 

discussed below. 

1. Radioimmunoassay (RIA) 

Advantages: established reliability. 

Disadvantages: assay time of 2hrs; rapid deterioration of reagents; handling precautions; 

needs a gamma counter; expensive; not suitable for a few samples a day; time consuming. 

2. Radial immunodiffusion (RID) 

Advantages: no sophisticated equipment required; convenient for a small number of 

samples. 

Disadvantages: assay time of 2 hrs. 

3. Nephelometry (NEPH) 

Advantages: wide range; assay time of ½ hr; simple calibration. 

Disadvantages: expensive equipment required. 

4. Immunoturbidimetry (IT) 

Advantages: assay time of 1 hr; wide range; least expensive. 

Disadvantages: requires multiple samples for standard curves with each assay. 

In summary, any of the 4 methods are suitable for routine use. Variation between methods 

however may influence comparison of results between laboratories or by different methods 

within the one laboratory. 

A number of groups have demonstrated that storage of frozen urine samples (for 2 weeks to 6 

months) at -20 o C results in lower measurements of microalbuminuria compared with freshly 

analysed samples (Elving et al, 1989; Osberg et al, 1990). However one group has reported 

that adequate mixing (3-4 hand inversions) after thawing of frozen aliquots resulted in the 

same albumin values as unfrozen aliquots measured by nephelometry (Innanen et al, 1997). 

This same group found however, that a small number of samples (2 to 9), despite mixing, 

gave falsely low urinary albumin results by up to 50%. It is postulated that freezing may 

distort the target albumin antigen in such a way that antibodies may not detect all of the 

albumin present. 

Studies of unfrozen urine samples stored at 4 o C for up to 8 weeks have shown no significant 

effect on urinary albumin (Osberg et al, 1990). It has also been reported that albumin in urine 

is stable when stored at room temperature for one week (Hara et al, 1994). In view of these 

findings, it is considered that urinary albumin measurement should either be analysed as fresh 


specimens or stored unfrozen at 4 o C and assayed within 8 weeks. Timed urine collection 

(either overnight or 24h) or a single void early morning urine sample should be obtained. 


Confounding factors in assessment of albuminuria 

Urinary albumin results can be affected by several confounding factors and the interpretation 

of albuminuria should take these into consideration. The following factors may affect urinary 

albumin results (Mogensen 1995; Mogensen et al, 1995). 

• Urinary tract infection 

• High dietary protein intake 

• Congestive heart failure 

• Acute febrile illness 

• Menstruation or vaginal discharge 

• Water loading 

• Drugs (NSAIDS, ACE inhibitors) 

In addition it is advisable to avoid assessing AER within 24 hours of high-level exercise or 

fever. 

Glomerular Filtration Rate 

An accurate measure of GFR can be undertaken using low molecular weight markers of 

kidney function such as inulin, iohexol or technetium (labelled DTPA), however the methods 

are time consuming, expensive and generally not available (Mathew & Australasian 

Creatinine Consensus Working Group 2005). In addition to direct measurement of GFR by 

isotopic methods there are several methods for estimating GFR. The measurement of 24h 

creatinine clearance tends to underestimate hyperfiltration and overestimate low GFR levels 

and is subject to errors in urine collection unless great care is taken. The regular 

measurement of serum creatinine levels is easy to perform and is currently the most common 

method. However because creatinine is invariably reabsorbed by the renal tubules, serum 

creatinine and creatinine clearance measurements tend to underestimate the GFR in the 

context of hyperfiltration and over estimate the GFR in the context of hypofiltration 

(Shemesh et al, 1985). 

In addition, for optimal approximation of GFR from serum creatinine measurements 

allowances need to be made for age, gender, height and weight of the individual. If the 

variables are taken into account, as in the Cockcroft-Gault (CG) and Modified Diet in Renal 

Disease (MDRD) equations, a satisfactory index of GFR can be achieved. This is particularly 

important in thin elderly female people whose baseline serum creatinine levels may be as low 

as 40-50 µM. In these people delay in referral until the serum creatinine rises above 110 µM 

would imply that more than 50% of kidney function had been lost (Levey et al, 1999). 

The 6 variable and 4 variable MDRD equations used for the estimation of GFR were 

developed from general populations (i.e. not specifically people with type 2 diabetes). The 6 

variable equation , which is the most commonly used equation for the estimation of GFR, 

was derived from the Modified Diet in Renal Disease study and includes the variables: 

creatinine, age, gender, race, serum urea nitrogen and serum albumin as follows (KDOQI 

2002): 

• eGFR = 170 x serum creatinine (mg/dl)-0.999 x age (yr)-0.176 x 0.762 (if female) x 1.18 

(if male) x serum urea nitrogen (mg/dl)-0.17 x albumin (g/l)+0.318 

The 6 variable MDRD equation correlated well with directly measured GFR (R 2 =90.3%). 

The modified 4 variable MDRD , again developed from general populations and not specific 

to people with type 2 diabetes is as follows (Levey et al, 1999): 


• eGFR = 186 x serum creatinine-1.154 x age -0.203 x 1.212 (if black) x 0.742 (if female) 

The 4 variable MDRD equation also correlated well with directly measured GFR 

(R 2 =89.2%). By contrast, 24h creatinine clearance or the Cockcroft-Gault equation 

overestimated subnormal GFR levels by 19% and 16% respectively (Levey et al, 1999; 

Manjunath et al, 2001). 

The position statement of the Australasian Creatinine Consensus Working Group recommend 

that an eGFR be automatically calculated and reported for every request for serum creatinine 

measurement in people of 18 years and over using the abbreviated MDRD equation (Mathew 

& Australasian Creatinine Consensus Working Group 2005). On the basis of survey and 

anecdotal information, the group considered that the vast majority of laboratory reports in 

Australia and New Zealand comply with this recommendation (Mathew et al, 2007). Some 

key aspects of the recommendations from the Australasian Creatinine Consensus Working 

Group are summarised below: 

• Pathology laboratories should automatically report eGFR calculated using the “175” 

MDRD formula, with every request for serum creatinine. 

• eGFR values over 90 mL/min/1.73 m2 should only be reported as > 90 mL/min/1.73 m2. 

• Pending further studies laboratories also should report eGFR for Australian Aboriginal 

and Torres Strait Islander peoples and other ethnic groups (previously no 

recommendation had been made). 

Measurement of serum cystatin C can be also used to estimate GFR. This may be more 

accurate than creatinine based eGFR methods particularly at normal levels (90-120 ml/min) 

or above normal levels (> 120 ml/min) but the assay is more expensive and is not yet 

generally available. Serial measurements of cystatin C levels have been shown to estimate 

progressive decline of GFR more accurately than creatinine based methods in both type 1 and 

type 2 diabetes. As with serum creatinine, the cystatin C is affected by factors other than the 

GFR and as with creatinine, knowledge of these factors is required in both estimating the 

GFR and interpretation of eGFR in particular populations. Currently the non GFR factors 

associated with cystatin C are poorly defined which limits the routine application of serum 

cystatin C in the estimation of GFR both in people with and without type 2 diabetes (e.g. 

Knight, 2004; Sjostrom, 2009; Stevens, 2008). The recent review by Stevens (2008) 

indicated many factors other than GFR to be associated with serum cystatin-C, including 

diabetes, measures of body size, higher C-reactive protein, higher white blood cell and lower 

serum albumin. The impact of these non GFR factors on serum cystatin C appear to be less 

than the non GFR influences on serum creatinine, however they remain poorly defined and 

may introduce significant variability within select sub populations. The recent study by 

Tidman et al (2008) concluded that the use of cystatin C only as “a determinator of eGFR 

does not yield improved accuracy” over estimation using the MDRD formula alone, however 

a formula that combines both serum creatinine and cystatin C may provide greater accuracy, 

consistent with the conclusions made by (Stevens, 2008). 


Evidence – Assessment of Kidney Function in Type 2 

Diabetes 

Microalbuminuria and CKD 

• Microalbuminuria is a key predictor for the development of CKD in people with 

type 2 diabetes, however CKD may develop in the absence of abnormalities in 

albumin excretion (Level II - Prognosis). 

Two retrospective studies in the early 1980s demonstrated that small increases in urinary 

AER predicted the development of overt nephropathy in people with type 1 diabetes 

(Mogensen & Christensen 1984; Viberti et al, 1982). This increase in AER was termed 

microalbuminuria and by consensus, referred to levels of AER of 20-200 µg/min in at lease 2 

of 3 samples. By comparison, in healthy subjects, AER ranges from 3-11 µg/min (Viberti et 

al, 1982) and routine dipstick tests do not become positive until AER exceeds 200µg/min 

(equivalent to total proteinuria of 0.5g/24h). Subsequent studies showed that 

microalbuminuria also predicts the development of clinical overt diabetic nephropathy in type 

2 diabetes (Mogensen 1984; Nelson et al, 1996) although it is not as strong a predictor as it is 

in type 1 diabetes. Persistent microalbuminuria confers an approximately 5 fold increase in 

the risk of overt nephropathy over 10 years in Caucasian persons with type 2 diabetes 

(approximately 20% cumulative incidence), compared with a 20 fold increase in risk of 

nephropathy in type 1 diabetes (approximately 80% cumulative incidence). However, in 

certain ethnic populations with a high prevalence of type 2 diabetes and diabetic nephropathy, 

including Pima Indians, Mexican Americans, African Americans, Maoris and Australian 

Aborigines, microalbuminuria is as strong a predictor of nephropathy as in type 1 diabetes 

(Hoy et al, 2001; Nelson et al, 1996; Pugh et al, 1995). 

The prospective cohort type study of 599 normoalbuminuric people with type 2 diabetes 

(Rachmani et al, 2000), found the baseline AER as a significant predictor of a subsequent 

decline in renal function as well as the risk of mortality and CVD (median follow up of 8 

years). 

The usefulness of microalbuminuria as a predictor of overt nephropathy in people with type 2 

diabetes is shown in the accompanying Table 5 adapted from Parving et al (2002). The 

studies selected in the are RCT trials of varying size and duration that the measured the 

progression of albuminuria as a primary outcome. Parving et al, (2002) concluded that the 

studies collectively show the value of microalbuminuria as a predictor of overt nephropathy 

based on the rate of development of overt nephropathy amongst the placebo groups. 


Table 5: Progression of microalbuminuria to overt nephropathy in people with 

type 2 diabetes. 

Study ID N Observation 

period (yrs) 

Individuals 

developing overt 

nephropathy (%/yr) 

Mogensen (1984) 59 9 2.4 

Nelson et al (1996) 50 4 9.3 

Ravid et al (1996) 49 5 8.4 

Gaede et al (1999) 80 4 5.8 

Ahmad et al (1997) 51 5 4.8 

Estacio et al (2000) 150 5 4.0 

The HOPE Study Group (2000) 1140 4.5 4.5 

Parving et al (2001) 201 2 7.5 

Parving (2001) 86 5 7.0 

Bruno et al (2003) 1253 

7 3.7 

(765 normoalbuminuria, 

488 microalbuminuria) 

Adapted from Parving et al (2002) 

Other prospective studies where the rate of decline in GFR was found to be enhanced in 

people with microalbuminuria are: 

• Murussi et al (2006) (n=65) –normoalbuminuric people with type 2 diabetes showed a 

similar rate of decline in GFR over a 10 year period (

In a retrospective cross sectional study of 301 adults with type 2 diabetes attending an 

outpatients clinic in Melbourne, the majority with reduced measured GFR (

Screening tests are designed to maximise true positive results (i.e. high sensitivity) at the 

expense of performing a greater number of confirmatory tests. Several studies have examined 

the relationship between AER and ACR performed on the same timed urine sample (Bakker 

1999; Connell et al, 1994; Hutchison et al, 1988; Shield et al, 1995; Wiegmann et al, 1990), 

however only 2 of these took gender into account (Bakker 1999; Connell et al, 1994). A 

number of studies have also compared ACR on a spot urine or early morning sample with a 

timed AER (Eshoj et al, 1987; Marshall & Alberti 1986; Nathan et al, 1987; Wiegmann et al, 

1990; Zelmanovitz et al, 1997) however none of these studies were stratified by gender. In 

these studies timed urine collections were used as the gold standard for comparison. Using 

the recommended cut-off values, the sensitivities of spot ACR in these studies were ≥ 88%. 

However different definitions for microalbuminuria on the timed collections (15-30µg/min) 

as well as varying definitions for a “positive” ACR level (2.0-4.5 mg/mmol) were used. 

Because of high intra-individual variability, transient elevations of AER into the 

microalbuminuric range occur frequently. The 95%CI for a sample with AER of 20 µg/min, 

assuming a coefficient of variation of 20%, are 12-28 µg/min (1 measurement), 14-26 µg/min 

(2 measurements) and 15-25 µg/min (3 measurements) (Tsalamandris et al, 1998). Therefore, 

clinical assessment should be based on at least 2 measurements taken over 3-6 months. 

Another option for assessment of albuminuria is the ACR which is usually performed on an 

early morning urine but can also be performed on a random sample. The use of ACR for 

assessment of microalbuminuria is easier and less time-consuming for the patient than 

measurement of AER. ACR measurements are particularly useful for screening purposes and 

for assessing the effects of treatment. For instance, measurements at every visit can be used 

to evaluate the albuminuric response separately from the blood pressure response during 

titration of antihypertensive therapy. Comparisons of ACR to the gold standard AER have 

been made in several studies. All the studies show satisfactory sensitivity (80-100%) and 

specificity (81-100%) (refer to Table 6 for summary). Table 6 includes a summary of the 

key components of the cross sectional studies in relation to the assessment of the applicability 

of ACR. 


Table 6: 

ACR – sensitivity and specificity for microalbuminuria screening 

Study ID 

Reference method for 

AER 

Reference 

level for 

AER 

ACR 

urine 

sample 

ACR result 

Sensitivity 

(%) 

Specificity 

(%) 

Bakker 

(1999) 


(overnight sample) 

20 µg/min Overnight 2.5 mg/mmol 

(female) 

1.8 mg/mmol 

(male) 

94 (female) 

94 (male) 

92 (female) 

93 (male) 

Gatling et al 

(1985) 

Hutchison et 

al (1988) 

Nathan et al 

(1987) 

Parsons et al 

(1999) 

Poulsen & 

Mogensen 

(1998) 

Micro-ELISA (overnight 

sample) 

Radioimmunoassay 


Radioimmunoassay (24 

hr sample) 

Immunoturbidimetry (24 

hr sample) 



AER 30 

µg/min 

AER 30 

µg/min 

44 

mg/24hr 

Early 

morning 

Early 

morning 

>3.5 mg/mmol 86 97 

>3.0 mg/mmol 97 94 

24 hr 3.4 mg/mmol 100 100 

20mg/l 24 hr 2.65 mg/mmol 95 79 

ACR 3.5 

mg/mmol 

(female), 

2.5 

mg/mmol 

(male) 

Not stated 

>3.5 mg/mmol 

(female) 

>2.5 mg/mmol 

(male) 

91 98 

A large study of people with type 2 diabetes from the United States showed that ACR, 

measured on a random urine sample, in the range 3.0 – 37.8 mg/mmol was over 88% 

sensitive and specific for the presence of microalbuminuria (Zelmanovitz et al, 1997). 

However it is important to note that the microalbuminuria range for ACR is influenced by 

both gender and age. There were approximately 30% false positives for ACR in people aged 

>65 years in a more recent study by Houlihan et al (2002c). For these reasons ACR has 

limitations as a diagnostic test but remains an excellent screening test for microalbuminuria. 

ACR performed on overnight urine samples has been reported in a number of studies as the 

least variable parameter (lowest co-efficient of variation) for measuring microalbuminuria. 

The coefficient of variation for the day to day variability or urinary creatinine excretion is in 

the range of 8-13% (Smulders et al, 1998) and 40-50% for AER (Feldt-Rasmussen et al, 

1985). As discussed by others, the reasons for this variability include changes in blood 

pressure, activity and fluid intake for albumin excretion, and changes in dietary protein intake 

for creatinine excretion (e.g Mogensen 1995 and Flynn et al, 1992). Previous studies have 

shown the intra-individual coefficient of variation for ACR to be 49% in first morning urine 

samples (McHardy et al, 1991) compared with 27% in timed overnight urine collections. 

ACR on overnight urine collections has been found to be the least variable parameter for the 

measurement of microalbuminuria (Harvey et al, 1999; Smulders et al, 1998). 

ACR is influenced by gender such that for a similar degree of albuminuria the ACR will be 

lower in males. Ageing has not been widely recognized as an important predictor of ACR 

and current guidelines only take gender into account as indicated in the review article by 

Mogensen et al (1995). In one study examining the inter-individual variability of urinary 

creatinine excretion and influence on ACR in people with diabetes, only gender and body 


mass index, but not age, were found to be significant determinants (Connell et al, 1994). In 

that study however, the individuals age range was relatively narrow at 36-68 years. In a more 

recent study in a clinic population with a wide age range (18-84 years) (Houlihan et al, 

2002c) and in one recent large study age was shown to have a significant effect on urinary 

creatinine excretion and on the relationship between ACR and AER (Bakker 1999). 

The gender specific microalbuminuria cut-off values for ACR of ≥2.5 mg/mmol and ≥3.5 

mg/mmol in males and females respectively are equivalent to an AER of 20 µg/min. These 

cut-off values have been supported in a study comparing timed overnight AER and ACR on 

the same sample in which the values of ACR corresponding to AER of 20µg/min were 2.4 

(95%CI: 2.2-2.7) in males and 4.0 (95%CI: 3.5-4.7) in females (Harvey et al, 1999). In the 

study of 314 patients, using regression analysis, a 24h AER of 20 µg/min yielded 24 hr ACR 

values of 2.5 (95%CI: 2.3-2.6) mg/mmol for males and 3.6 (95%CI: 3.4-3.7) mg/mmol for 

females. Spot ACR data, however produce higher ACR values at 20µg/min, and had wider 

confidence limits (Houlihan et al, 2002c). 

Age influences ACR such that for the same degree of albuminuria, ACR will increase with 

age. By definition, the ACR is dependent on albumin and creatinine excretion rates. The 

influence of age and sex on 24hr urinary creatinine is well established. For example, one 

large population-based Belgian study of over 4000 people (26-60 yrs) demonstrated 

significantly lower creatinine excretion in females and significant negative correlation of 

24 hr urinary creatinine excretion with age (Kesteloot & Joossens 1996). Therefore, increases 

in ACR with age can be explained in part by the age related changes in AER and 24 hr 

urinary creatinine excretion observed in both males and females. Normal ageing is 

characterised by a progressive decline in skeletal muscle mass and increase in body fat 

composition. Other age related factors that may influence ACR include the decline in 

skeletal muscle mass between the 20 – 80 years of age, which has been estimated to range 

from 22% up to 40% (Fleg & Lakatta 1988; Walser 1987), a decrease in the proportion of 

muscle in lean body mass (Walser 1987) and a lower meat intake in older subjects (Flynn et 

al, 1992). 

Bakker (1999) has proposed the use of age-specific cut off values for ACR to help restrict the 

number of people selected for follow up with timed urine collections. In this large study 

(n>2,300) an increase in the ACR cut-off for each decade, from age group 70 years, 

was required to maintain equivalent sensitivities and specificities in each age subgroup. 

However, the use of both gender and age-specific cut off values for ACR may be confusing 

and impractical. 

The clinical importance of an age-related increase in ACR is an increased false positive rate 

in older patients (e.g. decreased specificity). Using the recommended cut off values, the agerelated 

increase in false positive rates for spot ACR was approximately 30% for patients of 

either sex over 65 years (Houlihan et al, 2002c). 

Table 7 presents a summary of studies (including those discussed above) that provide 

evidence in relation to the use of AER and ACR for the screening and diagnosis of 

albuminuria. Included in the table is a summary of the key components of the cross sectional 

studies relevant to assessment of diagnostic accuracy. Where reported the sensitivity and 

specificity is shown along with the key conclusions made by the authors. It should be noted 

that only a few of the studies provided PPV and NPV values. 


Table 7: Summary of studies relevant to evidence for use of AER and ACR screening 

Study ID 

Study 

design 

and 

Setting 

Test 

Reference 

method(s) 

Ref 

level 

Urine 

sample 

Sensitivity 

(%) 

Specificity 

(%) 

PP 

V 

(%) 

NP 

V 

(%) 

Corr. 

Comments 

Ahn et al 

(1999) 

Cross 

sectional 

Korea 

n=105 

UAC, ACR 

AER, 

Immunonephelometry, 

24 hr 

RUS 

77, 77 (mic.) 

84, 88 (mac) 

82, 92 (mic.) 

90, 90 (mac) 

0.81, 0.75 Albumin measurements (UAC, 

UACR) in a RUS were 

considered as a valid test for 

screening diabetic nephropathy 

Bakker 

(1988) 

Cross 

sectional 

Netherland 

s 

n= 159 

ACR 

overnight, 

ALB 

albumin 

conc. 

AER 

Immunoturbidimetry, 

overnight 

20 

µg/min 

Overnight 

(F/M) 

94, 94 

89, 90 

(F/M) 

92, 93 

90, 89 

ACR performs better than ALD 

in screening for 

microalbuminuria, however the 

ACR needs sex- and agespecific 

discriminator values 

Cortes- 

Sanabria et 

al (2006) 

Cross 

sectional 

Mexico 

Micraltest II 

– morning 

AER Nephelometry, 

24hr 

Morning 83 96 95 88 0.81, P 2 

mg/mmol was the optimal 

screening test. 

Houlihan et 

al (2002c) 

Cross 

sectional 

Australia 

n=314 

ACR 

AER, 

immunoturbidimetry 24 

hr 

20 

ug/ml 

morning 

(F/M) 

93.35, 95.7 

The increase in spot ACR 

relative to 24 hr AER with age 

supports the use of sex- and 

age-adjusted cut off values for 

ACR. The clinical significance 

of the lack of age-adjusted cut 

off values for ACR is an 

increased false positive rate in 

older subjects (31.8% in men 

>65 years and 28.2% in women 

greater than 65 years). 


Study ID 

Study 

design 


Setting 

Test 

Reference 

method(s) 

Ref 

level 

Urine 

sample 

Sensitivity 

(%) 

Specificity 

(%) 

PP 

V 

(%) 

NP 

V 

(%) 

Corr. 

Comments 

Hutchison et 

al (1988) 

Cross 

sectional 

Scotland 

Albumin 

conc., ACR 

AER Radioimmunoassay 30 

µg/min 

First 

morning 

9.8 

96.8 

90.7 

93.9 

58.8 

68.2 

0.904 

0.921 

Either method was concluded 

to be acceptable as an initial 

screening procedure. 

n=276 

Incerti et al 

(2005) 

Cross 

sectional 

Brazil 

n=278 

Micraltest II 


24hr 

RUS 90 46 Measurement of UAC in a 

random urine specimen was the 

best choice for the diagnosis or 

screening of microalbuminuria. 

Jermendy et 

al (2001) 

Cross 

sectional 

n=192 

UAC, ACR 

UAE 

immunoturbidimetry 

First void 

79.3 (UAC) 

74.6 (ACR) 

69.5 (UAC) 

68.8 (ACR) 

Besides the standard 

measurement of UAE in timed 

urine samples, the use of 

convenient morning urinary 

spot collection could provide 

useful results. 

Mogensen et 

al (1997) 

Cross 

sectional 

Europe/U 

K 

n=2228 

Micraltest II 


microalbumi 

nuria 

Albumin concentration 

in urine. 


nephelometer, 

nephelometry 

20 

mg/l 

Spot, first, 

second 

morning 

sample 

96.7 71.0 0.78 0.95 Micral Test II permits an 

immediate and reliable semi 

quantitative determination of 

low albumin conc. In urine 

samples with an almost userindependent 

colour 

interpretation 

Mosca et al 

(2003) 

Cross 

sectional 

Italy 

n=87 

ACR 

AER 

Immunoturbidometry, 

timed overnight 

ACR is more suitable for 

monitoring albumin excretion 

in longitudinal studies than the 

AER. 

Mundet( X et 

al (2001) 

Cross 

sectional 

n=214 

ACR-first 

void 

AER 24 hr 0.93 P< 0.01 ACR is a useful method for 

diagnosis DN, depends on 

gender 


Study ID 

Study 

design 


Setting 

Test 

Reference 

method(s) 

Ref 

level 

Urine 

sample 

Sensitivity 

(%) 

Specificity 

(%) 

PP 

V 

(%) 

NP 

V 

(%) 

Corr. 

Comments 

Nathan et al 

(1987) 

Cross 

sectional 

US 

n= 25 

Single void 

AER 

Radioimmunoassay, 24 

hr 

20 

µg/ml 

94 96 0.82 P< 0.001 Single-void specimens adjusted 

for creatinine discriminate 

between normal and abnormal 

levels of microalbuminuria as 

determined in 24-h collection 

with high sensitivity and 

specificity. 

Parikh et al 

(2004) 

ABCD 

RCT 

US 

n= 326 

Micratest 

strips + urine 

specific 

gravity 

determinatio 

n (dipstick) 

AER 

immunoturbidimetry, 

timed collections 

≥ 30 

mg/d 

88 80 69 92 While the use of test strips 

provides a rapid approach to 

detecting microalbuminuria , 

the method has limitations. 

Zelmanovitz 

et al (1998) 

Cross 

sectional 

Brazil 

n= 167, 

217 urine 

samples 

Timed 24h 

urinary 

protein (UP), 

UPC, UPCR 

24h UAER I 

Immunoturbidometry, 

timed collections 

20 

µg/mm 

ol 

95.7, 92.9, 76.2 0.95, 0.77, 0.72 Protein measurement in spot 

urine is a reliable and simple 

method for screening and 

diagnosis of overt diabetic 

nephropathy 


Estimation of GFR 

• Estimation of GFR (eGFR) based on serum creatinine is a pragmatic, clinically 

relevant approach to assessing kidney function in people with type 2 diabetes 

(Level III - Diagnostic Accuracy). 

The Cockcroft-Gault and the MDRD formulas for the estimation of GFR were developed 

predominantly in individuals without diabetes. Studies involving people with type 2 diabetes, 

are summarised in Table 8 and are generally consistent with the findings for the large number 

of studies in non diabetes populations (KDOQI 2002). Nonetheless, the study by Rossing et 

al (2006) questioned the acceptability of the CG and MDRD equations for monitoring kidney 

function in individuals with type 2 diab etes. 

Table 8: 

GFR estimation studies with people with type 2 diabetes 

Study ID 

Fontsere et al 

(2006) 

Poggio et al 

(2005) 

Rossing et al 

(2006) 

Study 

Type 

Prospective 

cohort 

n = 87 

Cross 

sectional 

n = 249 

Prospective 

cohort 

n = 383 

Findings 

The best prediction equation compared to the isotopic method proved to 

be MDRD with a slope of GFR of -1.4/- 1.3 ml/min/yr compared with the 

CG formula -1.0 +/- 0.9 ml/min/yr. Creatinine clearance presented the 

greatest variability in estimation P

Summary – Assessment of Kidney Function in Type 2 

diabetes? 

• Regular monitoring of kidney function in people with type 2 diabetes is indicated by the 

high risk of development of CKD and the increased risk of CVD and mortality associated 

with increasing albuminuria and/or GFR

Evidence Tables: Section 1 

Assessment of Kidney Function 

a) Microalbuminuria and CKD 

Author (year) 

Evidence (Prognosis) 

Level of Evidence Quality Rating Magnitude of Relevance 

Level Study Type 

the effect Rating 

Rating 

Ahmad et al (1997) III-2 RCT High High Medium 

Bruno et al (2003) II Prospective Medium Medium Medium 

cohort 

Christensen et al 

II Prospective Low Medium Medium 

(1999) 

cohort 

Estacio et al (2000) III-2 RCT Medium High High 

Gaede et al (1999) IV RCT Medium Medium High 

Hoy et al (2001) II Prospective Medium High High 

cohort 

Kramer et al (2003) IV Crosssectional 

Medium Medium High 

MacIsaac et al (2004) IV Cross Medium High High 

sectional 

Murussi et al (2006) II Prospective Low Medium Medium 

cohort 

Murussi et al (2007) II Prospective Medium Medium Medium 

cohort 

Mogensen & 

II Prospective Medium High Low 

Christensen (1984) 

cohort 

Mogensen (1984) IV Case series Medium High High 

Nelson et al (1996) II Prospective Medium Medium Medium 

cohort 

Nosadini et al (2000) II Prospective Low Medium Medium 

cohort 

Parving (2001) IV RCT Low Low Medium 

Parving et al (2001) III-2 RCT High High High 

Pugh et al (1995) II Prospective Medium Medium Low 

cohort 

Rachmani et al (2000) II Prospective High High Medium 

cohort 

Ravid et al (1996) III-2 RCT Phase 1 High High High 

Open Phase 2 

Tsalamandris et al 

II Prospective Medium Medium Medium 

(1994) 

cohort 

The HOPE Study 

IV RCT High High High 

Group (2000) 

Viberti et al (1982) II Prospective 

cohort 

Medium High Low 


Author ( year) 

b) AER and ACR 

Evidence (Diagnostic Accuracy) 

Level of Evidence 

Magnitude of 

Quality 

the effect 

Level Study Type Rating 

Rating 

Relevance 

Rating 

Ahn et al (1999) III-2 Cross sectional Low Medium Medium 

Bakker (1988) 

III-3 

Diagnostic case 

control 

Medium Low Medium 

Bakker (1999) III-2 Cross sectional Medium High Medium 

Connell et al (1994) III-3 

Diagnostic case 

control 

Medium High High 

Cortes-Sanabria et al 

(2006) 

III-2 Cross sectional Low Medium Medium 

Eshoj et al (1987) IV Correlation study Medium Medium Medium 

Feldt-Rasmussen et al 

(1985) 

IV Correlation study Low Low Medium 

Gatling et al (1985) III-2 Cross sectional Low High Medium 

Gatling et al (1988) III-2 Cross sectional Low Low Medium 

Harvey et al (1999) IV 

Test method 

variability 

Medium Medium Medium 

Houlihan et al (2002c) III-3 Cross sectional Low Medium High 

Hutchison et al (1988) III-2 Cross sectional Low Medium Medium 

Incerti et al (2005) III-2 Cross sectional High High Medium 

Jermendy et al (2001) III-2 Cross sectional Low Medium Medium 

Kesteloot & Joossens 

(1996) 

III-2 Cross sectional Medium Medium Medium 

McHardy et al (1991) 

Test method 

IV 

reproducibility 

Medium Medium High 

Marshall & Alberti 

(1986) 

Cross sectional Low Medium Medium 

Mogensen et al (1997) III-2 Cross sectional Medium Medium Medium 

Mosca et al (2003) III-2 Cross sectional Low Medium High 

Mundet, X et al (2001) III-2 Cross sectional Low Medium Medium 

Nathan et al (1987) III-2 Cross sectional Low Low Medium 

Parsons et al (1999) III-2 Cross sectional Medium High High 

Parikh et al (2004) 

(ABCD) 

III-2 Cross sectional High Medium High 

Poulsen & Mogensen 

(1998) 

III-2 Cross sectional Low High High 

Shield et al (1995) III-2 Cross sectional Low Medium Medium 

Scheid et al (2001) 

III 

Systematic 

Review (of Level Medium Medium High 

III studies) 

Smulders et al (1998) IV Test variability Medium Medium High 

Tsalamandris et al 

(1998) 

III-2 Cross sectional Medium High Medium 

Wiegmann et al (1990) III-2 Cross sectional Low Medium Medium 

Zelmanovitz et al 

(1998) 

III-2 Cross sectional Medium Medium High 

Zelmanovitz et al 

(1997) 

III-2 Cross sectional Medium Medium High 


c) Estimation of GFR 

Author (year) 

Evidence (Diagnostic Accuracy) 

Level of Evidence Quality Magnitude of Relevance 

Level Study Type Rating the effect Rating 

Rating 

Fontsere et al (2006) III-2 Prospective High Medium High 

cohort 

Poggio et al (2005) III-2 Cross sectional Medium Medium High 

Rossing et al (2006) III-2 Prospective 

cohort 

High Low High 


Section 2: Prevention and/or Management of 

Chronic Kidney Disease 

Question 

How should chronic kidney disease be prevented and/or managed in people with type 2 

diabetes? 

i. What is the role of blood glucose control? 

ii. What is the role of blood pressure control? 

iii. What is the role of blood lipid modification? 

iv. What is the role of diet modification? 

v. What is the role of smoking cessation? 


Blood glucose control should be optimised aiming for a general HbA1c target ≤ 7%. 

(GRADE A). 

In people with type 2 diabetes and microalbuminuria or macroalbuminuria, ARB or 

ACEi antihypertensives should be used to protect against progression of kidney disease. 

(GRADE A) 

The blood pressure of people with type 2 diabetes should be maintained within the 

target range. ARB or ACEi should be considered as antihypertensive agents of first 

choice. Multi-drug therapy should be implemented as required to achieve target blood 

pressure. (GRADE A) 

People with type 2 diabetes should be informed that smoking increases the risk of 

chronic kidney disease (GRADE B) 


• The HbA1c target may need to be individualised taking in to account history of 

hypoglycaemia and co-morbidities. refer to “Blood Glucose Control in Type 2 

Diabetes” guidelines) 

• Systolic blood pressure (SBP) appears to be the best indicator of the risk of CKD in type 

2 diabetes. However, an optimum and safest lower limit of SBP has not been clearly 

defined. 

• Due to potential renoprotective effects, the use of ACEi or ARB should be considered 

for the small subgroup of people with normal blood pressure who have type 2 diabetes 

and microalbuminuria. 

• As there is limited evidence relating to effects of lipid treatment on the progression of 

CKD in people with type 2 diabetes, blood lipid profiles should be managed in 

accordance with guidelines for prevention and management of CVD. 



• Improving glycaemic control reduces the development and progression of kidney 

disease in people with type 2 diabetes. 

Evidence Level I – Intervention 

• Arterial hypertension is a key risk factor for kidney damage in people with type 2 

diabetes. 

Evidence Level I – Aetiology 

• In people with type 2 diabetes antihypertensive therapy with ARB or ACEi decreases 

the rate of progression of albuminuria, promotes regression to normoalbuminuria, and 

may reduce the risk of decline in renal function. 


• The extent to which interventions with lipid lowering therapy reduces the development 

of CKD is unclear. 


• There are insufficient studies of suitable quality to enable dietary recommendations to 

be made with respect to CKD in people with type 2 diabetes. 

Evidence Level II – Intervention 

• Smoking increases the risk of the development and progression of CKD in people with 

type 2 diabetes. 

Evidence Level II – Aetiology 


Background – Prevention and Management of Chronic 

Kidney Disease in Type 2 Diabetes 

It should be noted that the best way to prevent CKD in individuals with diabetes is to prevent 

diabetes. NHMRC recommendations for the primary prevention of type 2 diabetes are 

available elsewhere (www.diabetesaustralia.com.au). The present guidelines specifically 

target the management of individuals with established type 2 diabetes. 

The onset of type 2 diabetes is characterised by slow progressive increases in plasma glucose 

levels and is frequently associated with other risk factors for CVD such as elevated blood 

pressure, elevated AER’s, dyslipidaemia and smoking. 

A risk factor analysis for kidney dysfunction in type 2 diabetes following 15 years of follow 

up from the UKPDS study (Retnakaran et al, 2006), identified systolic blood pressure; 

urinary albumin excretion and plasma creatinine as common risk factors for albuminuria and 

kidney impairment (creatinine clearance and doubling of plasma creatinine). Additional 

independent risk factors for kidney impairment were female gender, decreased waist 

circumference, age, increased insulin sensitivity and sensory neuropathy. A cross-sectional 

study of 1003 Japanese type 2 diabetes hospital patients (Hanai et al, 2008) used logistic 

regression to identify large waste circumference and elevated blood pressure as risk factors 

for microalbuminuria while dyslipidaemia was identified as a risk factor for decreased GFR. 

In contrast to type 1 diabetes, only 20% of newly diagnosed people with type 2 diabetes are 

normotensive and have a normal circadian blood pressure profile. Therefore hypertension 

usually precedes the onset of microalbuminuria (Mogensen et al, 1983). Blood pressure 

control modulates the progression not only of microangiopathy (diabetic kidney disease and 

retinopathy) but also of macroangiopathy (CHD and stroke). 

In microalbuminuric people with type 2 diabetes, observational studies have shown an 

association between poor glycaemic control and progression of albuminuria. A number of 

studies have identified a strong independent association between hyperglycaemia and the rate 

of development of microvascular complications (Newman et al, 2005). The large 

observational WESDR study (Klein et al, 1996) indicated an exponential relationship 

between worsening glycaemic control and the incidence of nephropathy as well as 

retinopathy and neuropathy. 

The UKPDS has clearly shown the importance of targeting glycosylated haemoglobin 

(HbA1c) levels close to normal (HbA1c 34 mg/mol (Tapp et al, 2004). The prevalence of albuminuria increased with increasing 

glycaemia. People with diabetes and impaired glucose tolerance had an increased risk for 

albuminuria compared to those with normal glucose tolerance, independent of other known 

risk factors for albuminuria (including age and sex). 


Hyperglycaemia is an important determinant of the progression of normoalbuminuria to 

microalbuminuria in diabetes. Strict blood glucose control has been shown to delay the 

progression from normoalbuminuria to microalbuminuria or overt kidney disease (UKPDS 

1998c) and from normo- or microalbuminuria to overt kidney disease (Ohkubo et al, 1995). 

The influence of intensive glycaemic control is greatest in the early stages of CKD although 

some observational studies suggest an association of glycaemic control with the rate of 

progression of overt kidney disease and even ESKD (Morioka et al, 2001). 

The American Heart Association (AHA) has undertaken a review of the DCCT, UKPDS, 

ACCORD, ADVANCE and VA Diabetes trials and on the basis of the review issued a 

Scientific Statement addressing intensive glycaemic control in relation to cardiovascular 

events (Skyler et al, 2009). The AHA review is focused on cardiovascular events, however, 

the statement is relevant to the consideration of the management of CKD given the strong 

association between CKD and CVD in people with type 2 diabetes. Consistent with the 

evidence reviewed in these guidelines [refer to following sections], the AHA note that a small 

but incremental benefit in microvascular outcomes (principally renal outcomes) is indicated 

with HbA1c values approaching normal. As a consequence the AHA statement notes that on 

the basis of findings from the DCCT, UKPDS and ADVANCE trials some patients may 

benefit (in terms of microvascular outcomes) from HbA1c goals lower than the general goal 

of

3) Attenuation of the rate of decline of GFR when compared to a control group treated 

with other antihypertensive agents in equihypotensive doses 

However, that inclusion of proteinuria is a weaker basis for identifying renoprotective 

treatments than a reduction in the rate of decline of GFR (Mogensen 1999). 

Several studies have documented the efficacy of antihypertensive therapy in lowering AER in 

both hypertensive (Chan et al, 1992; Ferder et al, 1992; Slataper et al, 1993) and people with 

type 2 diabetes and microalbuminuria who are normotensive (Ahmad et al, 1997). 

People with type 2 diabetes and kidney disease show a broad range of lipid abnormalities, 

characterised by a switch to a more atherogenic lipid profile. This becomes more pronounced 

with increasing proteinuria, although several factors such as glycaemic control, insulin 

administration, obesity and genetic factors may alter the degree of dyslipidaemia. 

Increased levels of triglycerides are consistently seen in people with type 2 diabetes and 

microalbuminuria or overt proteinuria (Bruno et al, 1996; Mattock et al, 1992; Nielsen et al, 

1993). The high triglyceride levels are associated with an increased proportion of atherogenic 

small dense LDL cholesterol particles (Lahdenpera et al, 1996). The implication is that serum 

triglycerides should be as low as possible to prevent atherogenic changes in LDL-cholesterol 

particles (Groop et al, 1993). HDL cholesterol levels in people with type 2 diabetes have been 

reported to be normal in association with overt diabetic kidney disease (Nielsen et al, 1993) 

whereas decreased HDL-cholesterol levels have been reported in association with 

microalbuminuria (Mattock et al, 1992). Higher apolipoprotein (a) levels have been reported 

in people with type 2 diabetes and micro- and macroalbuminuria than in control subjects, and 

also in people with macroalbuminuria than with normoalbuminuria (Jenkins et al, 1992). 

Apolipoprotein (a) levels have been related to the rates of progression of albuminuria (Jerums 

et al, 1993), however, others have not confirmed these findings in people with diabetes and 

CKD (Nielsen et al, 1993). 

There is evidence to support the hypothesis that changes in lipid profiles may play a causal 

role in the initiation and progression of kidney disease, based on the finding of lipid deposits 

and foam cells in the glomeruli of humans with kidney disease (Keane et al, 1988). 

Primary or secondary intervention with statins in hypercholesterolaemic people has shown 

similar cardioprotective effects in diabetic and non-diabetic subjects (Pyorala et al, 1997; 

Sacks et al, 1996; Shepherd et al, 1995). The absolute clinical benefit achieved by cholesterol 

lowering may be greater in people with CHD and diabetes than with CHD and without 

diabetes because people with diabetes have a higher absolute risk of recurrent CHD events 

and other atherosclerotic events (Pyorala et al, 1997). 

Observational studies have shown that dyslipidaemia interacts with other risk factors to 

increase cardiovascular risk (Kannel 1996; Stamler et al, 1993). Microalbuminuria is a risk 

factor for CVD as well as overt kidney disease in people with type 2 diabetes (Mogensen 

1984; Schmitz & Vaeth 1988), and dyslipidaemia is more common in microalbuminuric than 

normoalbuminuric people with type 2 diabetes (Mattock et al, 1992). In people with type 1 or 

type 2 diabetes and increased AER, elevated LDL-cholesterol and triglycerides are common, 

whereas HDL-cholesterol may be high, low or normal. Nearly all studies have shown a 

correlation between serum cholesterol concentration and progression of CKD (Parving 1998; 

Smulders et al, 1997b). Since increased AER and dyslipidaemia are each associated with an 

increased risk of CHD, it is logical to treat dyslipidaemia aggressively in people with 

increased AER. Subgroups with diabetes in large intervention studies have confirmed that 

correction of dyslipidaemia results in a decrease in CHD (National Heart Foundation of 


Australia 2001). However, few trials have examined the effects of treating dyslipidaemia on 

kidney end-points in people with type 2 diabetes and increased AER. Further studies are, 

therefore, required in people with microalbuminuria and macroalbuminuria in order to assess 

the effects of statins and fibrates on albuminuria and kidney function. Until the results of this 

type of study are known, it will not be possible to determine if correction of dyslipidaemia 

alone exerts renoprotective effects. Furthermore, it is not known if intervention with specific 

agents such as statins or fibrates exerts effects on kidney end-points over and above 

protection from cardiovascular events. 

Dyslipidaemia is a common finding in individuals with type 2 diabetes, particularly those 

with CKD, in whom it is a significant risk factor for adverse cardiovascular outcomes 

(Kannel 1996; Mattock et al, 1992; Stamler et al, 1993) (refer also to the NHMRC guidelines 

for the prevention of cardiovascular disease in type 2 diabetes). Moreover, the lowering of 

LDL cholesterol in individuals with type 2 diabetes leads to primary and secondary 

prevention of cardiovascular events and mortality (Costa et al, 2006). The absolute risk 

benefit of lipid lowering is much larger reflecting the increased absolute risk of adverse 

cardiovascular outcomes. 


Evidence – Prevention and Management of Chronic Kidney 

Disease in Type 2 Diabetes 

i) Role of Blood Glucose Control 

• Improving glycaemic control reduces the development and progression of 

kidney disease in people with type 2 diabetes (Evidence Level I – 

Intervention). 

The issue of the role of blood glucose control in the development and progression of kidney 

disease in individuals with type 2 diabetes has been addressed by a number of systematic 

reviews and RCTs. A summary of relevant studies is presented in Table 9 with key studies 

discussed in the text below. Whilst a number of these studies have examined the use of 

specific antihyperglycaemic agents, it is not possible on the basis of the current evidence to 

provide recommendations of the use of specific agents in relation to the progression of CKD. 

The systematic review by Newman et al (2005) addressed the question of whether improved 

glycaemic control reduces the rate of development of secondary diabetic complications in 

people with either type 1 or type 2 diabetes and microalbuminuria. Five RCTs were 

identified in people with type 2 diabetes. The review considered ESKD, eGFR and clinical 

proteinuria with the following outcomes: 

• No RCT evidence was identified to show that improved glycaemic control has any effect 

on the development of ESKD. The most relevant study is the UKPDS from which further 

information may come from long-term follow up. 

• Evidence from the VA Cooperative study (Levin et al, 2000) indicate that intensified 

glycaemic control has little if any effect on the rate of GFR decline. 

• Three studies were identified in relation to improved glycaemic control and the 

development of clinical proteinuria and microalbuminuria, namely the Kumamoto study 

(Shichiri et al, 2000), UKPDS (UKPDS 1998c) and the VA Cooperative study (Levin et 

al, 2000). These studies provide some evidence that intensive treatment of 

hyperglycaemia in normoalbuminuric people with type 2 diabetes will, in a proportion of 

people, prevent development of microalbuminuria and provide some evidence of a 

reduction in the rate of clinical proteinuria. However, the studies only included a 

proportion of people with microalbuminuria. The VA study examined as a sub group the 

effect of glycaemic control in those with microalbuminuria, however the study was 

relatively small and of limited duration. 

The systematic review by Richter et al (2006) assessed the effects of pioglitazone in the 

treatment of type 2 diabetes. The relevant outcomes for these guidelines are mortality 

(kidney disease) and morbidity (nephropathy). Overall the evidence for a positive patientoriented 

outcome for the use of pioglitazone was considered not to be convincing. Three 

studies were identified that included endpoints relevant to the assessment of kidney disease 

namely, Hanefeld et al (2004), Matthews et al (2005) and Schernthaner et al ( 2004). The 

Hanefeld et al (2004) study compared pioglitazone plus sulfonyl urea with metformin plus 

sulphonyl urea over 12 months in 649 people with type 2 diabetes with a history of poorly 

controlled diabetes. The pioglitazone treatment resulted in a 15% reduction in the urinary 

ACR compared to a 2% increase in the metformin group with both treatments giving 

clinically equivalent glycaemic control. The Matthews et al (2005) study compared 

pioglitazone plus metformin with glicazide plus metformin in 630 people with poorly 

managed type 2 diabetes over 12 months. The pioglitazone treatment gave a 10% reduction 


in the ACR compared to a 6% increase in the glicazide group with no significant difference in 

HbA1c. 

The Schernthaner et al (2004) study of 1199 people with type 2 diabetes inadequately treated 

by diet alone (HbA between 7.5% and 11%) and aged between 35-75 years from 167 centres 

located across 12 European countries. Pioglitazone treatment resulted in a 19% decrease in 

ACR compared to 1 % in the metformin group. Blood pressure was not statistically different 

between groups. The results were considered to be consistent with previous studies that 

troglitazone but not metformin or glibenclamide reduced urinary albumin excretion rate. 

The systematic review by Richter et al (2007) assessed the effects of rosiglitazone in the 

treatment of type 2 diabetes. The study by Lebovitz et al (2001) was identified as including 

an outcome measure relevant to kidney disease. The study examined the use of rosiglitazone 

as a monotherapy in 493 people with type 2 diabetes over a 7 month period. Urinary albumin 

excretion was decreased significantly compared to the placebo. For the subgroup of people 

with microalbuminuria, both doses of rosiglitazone gave a reduction in ACR from baseline of 

around 40%. Only a small percentage of patients were receiving antihypertensive therapy 

which the authors suggested indicates the effect to be a result of improved glycaemic control 

or a different effect of rosiglitazone. The measurement of urinary ACR was a secondary 

prospective outcome of the study of 203 people with type 2 diabetes by Bakris et al (2003) 

comparing rosiglitazone with glyburide in a randomised controlled trial. RSG significantly 

reduced ACR from baseline and strongly correlated with changes in blood pressure and little 

relation to changes in FPG or HbA1c. Given similar levels of glucose control, the mean 

reduction in ACR was greater for rosiglitazone than glyburide and a greater proportion of 

participants in the RSG treatment group with baseline microalbuminuria achieved 

normalisation of the ACR by the 12 months. However, the power of the study in relation to 

the secondary outcome (ACR) was low and the differences in between the groups was not 

statistically significant, thus the suggested potential benefit of RSG cannot be determined 

from this study. 

The objectives of the systematic review by Saenz et al (2005) were to assess the effects of 

metformin monotherapy on mortality, morbidity, quality of life, glycaemic control, body 

weight, lipid levels, blood pressure, insulinaemia and albuminuria in people with type 2 

diabetes. The review identified only one small trial of 51 people with type 2 diabetes with 

incipient nephropathy with 3 month follow up (Amador-Licona et al, 2000), which reported 

some benefit for microalbuminuria with metformin treatment. The authors concluded that 

microalbuminuria should be incorporated into the research outcomes and no overall 

conclusion has been made with respect to effects of metformin on diabetic kidney disease. 

In addition to the studies identified by Saenz et al (2005), the HOME trial (De Jager et al 

2005) examnined the efficacy of metformin in 345 people with type 2 diabetes over a four 

month period. Metformin was associated with a 21 % increase in the UAE compared to the 

placebo, the authors considered this to be a short term anomaly given the association of UAE 

with HbAc1, however they were unable to identify the reason for the anomaly. 

The ADVANCE trial (ADVANCE 2008) was designed to assess the effects on major 

vascular outcomes of lowering the HbAc1 to a target of 6.5% or less in a broad cross-section 

of people with type 2 diabetes with CVD or high risk of CVD. The primary endpoints were a 

composite of both macrovascular and microvascular events. Endpoints relevant to kidney 

disease included development of macroalbuminuria, doubling of serum creatinine, the need 

for renal replacement therapy or death due to kidney disease. At baseline approximately 27% 

of the participants had a history of microalbuminuria and 3 to 4 % had macroalbuminuria. At 

the end of the follow up period the mean HbAc1 was significantly lower in the intensive 


group (6.5%) than the standard group (7.3%). The mean systolic blood pressure was on 

average 1.6 mm Hg lower than the standard group. 

A significant reduction (hazard ratio 0.86 CI 0.77 to 0.97) in the incidence of major 

microvascular events occurred, while macrovascular events were not significantly different 

between the groups. Intensive glucose control was associated with a significant reduction in 

renal events including new or worsening of nephropathy (HR 0.79; CI 0.66 – 0.93) 

predominantly due to a reduction in the development of macroalbuminuria and new onset 

microalbuminuria (0.91 CI 0.85 – 0.98). A trend towards a reduction in the need for renal 

replacement therapy was also noted. The study concluded that the lack of a significant effect 

on major macrovascular events may be due to inadequate power to detect such an effect 

given a lower than expected rate of macrovascular events. Some but not all of the overall 

effect on major events could be attributed to the small but significant 1.6 mm Hg lower SBP 

in the intensive group (ADVANCE 2008). 

A significantly higher number of severe hypoglycaemic episodes was recorded in the 

intensive group compared to the standard group (2.7% vs. 1.5%). The rates were 0.7 severe 

events per 100 people in the intensively controlled group and 0.4 severe events per 100 

people in the standard control group. The rates for minor hypoglycaemic events were 120 per 

100 people in the intensively controlled group compared to 90 per 100 people in the standard 

control group. Overall the main benefit identified by the ADVANCE study was a one fifth 

reduction in kidney complications in particular the development of macroalbuminuria 

(ADVANCE 2008). 

A US study of Hispanic and African Americans assessed the efficacy of rosiglitazone in a 

high risk (based on ethnicity) type 2 diabetes group (Davidson et al, 2007). The urinary ACR 

was collected as a secondary outcome under the general grouping of CVD markers. The 

study included 245 people with type 2 diabetes with FPG greater than or equal to 140 mg/dL 

and HbA1c greater than or equal to 7.5% who had been on a sulphonyl urea monotherapy for 

a minimum of 2 months and were randomized to receive glyburide (GLY) plus rosiglitazone 

(RSG) or glyburide (GLY) plus placebo for 6 months. The urinary ACR was reduced by 

26.7% in the treatment group (GLY+RSG) compared to control group (GLY+ placebo). 

Improved insulin sensitivity and β-cell function with thiazolidinedione treatments was also 

noted. 

US studies on the long term effectiveness of miglitol have been conducted by Johnston and 

colleagues for 385 Hispanic Americans with type 2 diabetes and 345 African Americans with 

type 2 diabetes (Johnston et al (1998a) and Johnston et al (1998b) respectively). ACR was 

included as an “efficacy parameter” in both studies. The duration of the studies was 12 

months. Miglotol treatment was associated with a minor reduction in ACR in both studies. 

The short term trial of 223 mixed type 1 and type 2 diabetes by Gambaro et al (2002), 

reported significant improvement in albuminuria in those with micro or macroalbuminuria 

following a 4 month high dose treatment with sulodexide. The effect was considered to be 

additive to the ACE inhibitory effect. The sub analysis by diabetes type produced similar 

results. 

The multifactorial intensive treatment of the STENO2 study (Gaede et al 2003b) reduced the 

risk of nephropathy by 50%. This long term study (mean 7.8 years) of 160 people with type 

2 diabetes and microalbuminuria, utilized multifactorial interventions for modifiable risk 

factors for cardiovascular disease which included intensive treatment of blood glucose. 

Whilst a the intensive treatment group achieved a significantly lower blood glucose 

concentration, given the multifactorial nature of the study it is not possible to determine the 


elative contribution that intensive blood glucose control may have had on the renal 

outcomes. 

Table 9 presents a summary of studies that provide evidence in relation to the role of blood 

glucose control. The summaries are provided as an overview of the evidence. 


Table 9: 

Summary of studies relevant to the assessment of the role of glucose control in CKD in individuals with type 2 diabetes 

Study ID Study Description Intervention Outcome 

(relevant to CKD) 

ADVANCE 

(2008) 

RCT 

Multicentre (215 across 20 countries) 

Type 2 diabetes diagnosed at 30 

years or older. Age >=55 years at the 

start of the study. History of major 

vascular or microvascular disease or 

at least one other risk factor for 

vascular disease. 

n=11,000 

Intensive blood 

glucose control 

(target



Davidson et 

al, (2007) 

De Jager et 

al (2005) 

HOME 

Gaede et al 

(2003b) 

Steno2 

Gambaro et 

al (2002) 

Hanefeld et 

al (2004) 

Johnston et 

al (1998a) 

Johnston et 

al (1998b) 

RCT, double blind, placebo 

controlled 

US Multicentre (38), US Hispanic 

and African American 

Type 2 diabetes, FPG > or = 140 

mg/dL and HbA(1c) >=7.5%, 

monotherapy with sulfonyl urea for a 

minimum of 2 months 

n=245. 

RCT 

Netherlands – 3 centres 

Type 2 diabetes 

n=345 

RCT 

Type 2 diabetes, microalbuminuria 

n=160 


Multicentre 

Type 1 diabetes and Type 2 diabetes, 

micro or macroalbuminuric 

n=223 

RCT, double blind 

Multicentre 

Type 2 diabetes, inadequately 

managed 

n=649 

RCT 

Type 2 diabetes, Hispanic 

n=385 

RCT 

Type 2 diabetes, African-American 

n=345 

Glyburide + 

Rosiglitazone vs. 

Glyburide + 

Placebo 

Metformin plus 

insulin vs. 

Placebo plus 

insulin 

Multifactorial 

intensive 

treatment vs. 

Standard 

treatment 

Suloexide vs. 

Placebo 

Pioglitazone plus 

SU vs. 


SU 

Miglitol vs. 

Placebo 

Miglitol vs. 

Placebo 

ACR (secondary 

and as a CVD risk 

marker). 

Follow Comments/Conclusions 

up 

(mths) 

6 ACR reduced by 26.7% in treatment group (GLY+RSG) compared to 

control group (GLY+ placebo). Improved insulin sensitivity and β-cell 

function with thiazolidinedione treatments. 

UAE 4 Metformin treatment was associated with a 21% increase in UAE 

compared to the placebo. However considered a short anomaly as UAE 

shown to be associated with HbAc1 

UAE 94 

(mean) 

Target driven long-term intensified treatment aimed at multiple risk 

factors reduced nephropathy by about 50%. 

UAE 4 Significantly reduced albuminuria in people with both type 1 and type 2 

diabetes. 

ACR 12 Clinically equivalent improvements in glycaemic control. Pioglitazone 

plus SU resulted in a reduction of ACR. Overall differences from 

baseline ACR small (i.e.



Lebovitz et 

al (2001) 

Levin et al 

(2000) 

Matthews et 

al (2005) 

Ohkubo et al 

(1995) 

Schernthane 

r et al (2004) 

Shichiri et al 

(2000) 

Kunamoto 

Study 

RCT 

Multicentre (42), US, mixed race. 

Type 2 diabetes, 36-81 years, FPG 

(7.8-16.7 mmol/L), BMI between 22- 

38 kg/m 2 , no renal impairment or 

DN. 

n=493 

RCT 

Type 2 diabetes (mean age 60, mean 

duration of diabetes 8 years) 

n=153 


Type 2 diabetes, poorly managed 

n=630 

RCT 

Japan 

Type 2 diabetes, divided into primary 

prevention and secondary 

intervention cohorts on the basis of 

albuminuria and retinopathy. 

n=110 

RCT, double-blind 

Multicentre, 167 centres across 12 

European countries 

Type 2 diabetes inadequately treated 

by diet alone (HbA between 7.5% 

and 11%), 35-75 years 

n=1199 

RCT 

n=110 

Rosiglatzone ( 2 

or 4 mg/day) vs. 

Placebo 

Intensive (HbA1c 

goal 7.1%) vs. 

Standard (HbA1c 

goal 9.1%) 


pioglitazone vs. 


gliclazide 

Multiple Insulin 

Treatment (MIT) 

vs. 

Conventional 

Insulin Treatment 

(CIT) 

Pioglitazone vs. 

Metformin 

MIT vs. 

CIT 

Follow 

up 

(mths) 

Comments/Conclusions 

UAE, ACR 7 ACR decreased significantly in both 2 and 4 mg/day RSG. Compared 

with an insignificant increase from baseline of the placebo. For 

subgroup with microalbuminuria, both doses of RSG gave reduction in 

ACR from baseline of around 40%. Only a small percentage of patients 

were receiving antihypertensive therapy – suggests effect is a result of 

improved glycaemic control or a different effect of RSG. 

UAE, ACR 24 Intensive glycaemic control retarded microalbuminuria, but may not 

lessen the progressive deterioration of glomerular function. 

ACR 12 Mean ACR reduced by 10% in met plus piog group. Potential benefits 

are indicated. 

UAE 60 Intensive glycaemic control can delay the onset and progression of 

nephropathy. 

The cumulative percentages of the development and the progression in 

nephropathy after 6 years were 7.7% for the MIT group and 28.0% for 

the CIT group in the primary-prevention cohort (P = 0.032) 

ACR 12 Pioglitazone – 19 % decrease in ACR compared to 1 % in metformin 

group. BP not statistically different between groups. Consistent with 

previous studies that troglitazone but not metformin or glibenclamide 

reduced urinary albumin excretion rate. 

Albuminuria 96 Intensive glycaemic control (MIT) – cumulative percentages of 

worsening in nephropathy were significantly lower. 


ii) 

Role of Blood Pressure Control 

a) Blood Pressure as a Risk Factor for CKD 

• Arterial hypertension is a key risk factor for kidney damage in people with 

type 2 diabetes Evidence (Level I – Aetiology). 

Several trials have clearly shown that intensive treatment of elevated blood pressure lowers 

the risk of microvascular disease, CVD and mortality in type 2 diabetes (refer to systematic 

reviews of Kaiser et al (2003), Newman et al (2005), Strippoli et al (2005) and Strippoli et al 

(2006). 

The UKPDS has been the largest long-term study to compare the effects of intensive vs. less 

intensive blood pressure control in hypertensive people with type 2 diabetes. In this 9-year 

study of 1148 people, allocated to tight blood pressure control (n=758) or less tight control 

(n=390), mean blood pressure was significantly reduced in the tight control group (144/82 

mmHg), compared with the group assigned to less tight control (154/87 mmHg) (p

) Blood Pressure Control for Prevention and Management of CKD 

• In people with type 2 diabetes antihypertensive therapy with ARB or ACEi 

decreases the rate of progression of albuminuria, promotes regression to 

normoalbuminuria, and may reduce the risk of decline in renal function 

(Evidence Level I – Intervention). 

A large number of systematic reviews and trials have examined antihypertensive therapy 

using ACEi and ARBs in people with type 2 diabetes. A summary of relevant studies is 

shown in Table 10 with findings of key studies described in the text below. 

Systematic reviews and meta-analyses: 

The systematic review of RCTs up until 2002 reported by Newman et al (2005) examined 

three areas relevant to consideration of the use of antihypertensive therapy that are 

summarised below: 

1. Antihypertensive therapy and development of ESKD in people with type 2 diabetes and 

microalbuminuria. 

Only three RCTs were identified as being of sufficient size and length of follow up namely 

ABCD, UKPDS and HOPE. Of these ABCD did not include ESKD as an endpoint. 

• In the UKPDS study the prevalence of ESKD was less than 2 % with a relative risk for 

tight control of 0.58 (95% CI 0.015 to 2.21) with similar results for death from kidney 

failure (UKPDS 1998d). 

• The HOPE Study demonstrated that there was a non significant relative risk reduction for 

the requirement for renal dialysis amongst people treated with ramipril (The HOPE Study 

Group 2000). 

As a consequence he above two trials, Newman et al (2005) concluded that there was no 

evidence of a beneficial effect of antihypertensive therapy on the development of ESKD. 

2. Antihypertensive therapy and change in GFR in people with type 2 diabetes and 


Three placebo controlled trials in normotensive people were identified namely Ahmad et al 

(1997), Ravid et al (1993) and Sano et al (1996). Newman et al (2005) conclude that the data 

are inconclusive. No appropriate trials comparing different antihypertensive agents and 

intensive versus moderate blood pressure control were identified. However, later analysis of 

the ABCD trial (Schrier et al, 2002) indicated a significant effect of intensive therapy on the 

progression from microalbuminuria to clinical proteinuria, however there was no change in 

creatinine clearance and no difference between ACEi and CCB. 

Two placebo controlled trials in hypertensive people were identified namely Lebovitz et al 

(1994) and Parving et al (2001). Newman et al (2005) conclude that the limited evidence 

indicates kidney function to remain stable in hypertensive people with type 2 diabetes with 

microalbuminuria treated with ACEi compared to a decline in the placebo group (36 month 

follow up). The Parving et al (2001) study also indicated a significant reduction in the rate of 

progression to clinical proteinuria with ARB treatment however this was not associated with 

significant decline in creatinine clearance. 


Two trials were identified that compared intensive and moderate blood pressure control in 

hypertensive people with type 2 diabetes with microalbuminuria, namely ABCD (Estacio et 

al, 2000) and UKPDS (UKPDS 1998d). However, the UKPDS study was unable to 

differentiate between normoalbuminuric and microalbuminuric subgroups. In the large 

ABCD study no significant difference in creatinine clearance was found in either 

normoalbuminuric or microalbuminuric subgroups. 

Three appropriate trials were identified comparing different antihypertensive agents in 

hypertensive people with type 2 diabetes with microalbuminuria namely Agardh et al (1996), 

Estacio et al (2000) and Lacourciere et al (1993). None of these trials showed significant 

differences in GFR or creatinine clearance. 

3. Antihypertensive therapy and development of clinical proteinuria in people with type 2 

diabetes and microalbuminuria. 

Three randomised placebo-controlled trials in normotensive people with type 2 diabetes with 

microalbuminuria were identified namely, Ahmad et al (1997), Ravid et al (1993) and Sano et 

al (1996). These three trials all used the ACEi enalapril as the treatment. The overall relative 

risk for the development of proteinuria for the three trials was 0.28 (95% CI 0.15 to 0.53) 

with no significant heterogeneity between studies. No study provided information to allow 

assessment of regression to normoalbuminuria. The overall risk reduction was 4.5% giving a 

NNT of 22 patients per year to prevent one case of clinical proteinuria. The differences in 

blood pressure between treatment and placebo were small and as such Newman et al (2005) 

consider that a 72% drop in clinical proteinuria was unlikely to be caused by such a small 

difference and more likely that ACEi have a specific renoprotective effect. 

No appropriate trials were identified comparing antihypertensive agents and intensive versus 

moderate blood pressure control with the exception of later analysis of the ABCD trial. 

Intensive therapy with either enalapril or nisoldipine resulted in a lower percentage of people 

who progressed from normoalbuminuria and microalbuminuria to clinical proteinuria with no 

difference between the ACEi or the CCB (Estacio et al, 2000). 

Only one available placebo controlled study was identified for hypertensive people with type 

2 diabetes with microalbuminuria (Parving et al, 2001). The treatment involved two dose 

levels of the ARB antagonist irbesartan for two years. A combined relative risk for clinical 

proteinuria for the ARB treatments was 0.50 (95% CI 0.0.31 to 0.81). This reduction in the 

rate of progression to clinical proteinuria was independent of blood pressure. 

Only the ABCD trial (Estacio et al, 2000) was identified as being relevant for comparing 

intensive versus moderate blood pressure control in hypertensive people with type 2 diabetes 

with microalbuminuria. Individuals were randomised to either ACEi enalapril or the CCB 

antagonist nisoldipine. The percentage of people who progressed from microalbuminuria to 

clinical proteinuria was not significantly different between the treatment groups. Newman et 

al (2005) noted that the results supported the observations from the UKPDS of progression to 

clinical proteinuria amongst microalbuminuric and normoalbuminuric people with type 2 

diabetes was not affected by the level of blood pressure control, however separation of the 

two groups is not possible. 

Four trials were identified comparing different hypertensive agents in hypertensive people 

with type 2 diabetes with microalbuminuria namely Agardh et al (1996), Chan et al (2000), 

Estacio & Schrier (1998) and Lacourciere et al (1993). The trials all included an ACEi 

treatment compared with either a CCB antagonist or β blocker. The overall relative risk of 


development of clinical proteinuria for ACEi versus other hypertensive therapy was 0.74 

(95% CI 0.44 to 1.24) with no significant heterogeneity. Thus the ACEi reduced progression 

to clinical proteinuria as effectively as the other therapies. These findings were considered to 

be comparable with the UKPDS findings which could not separate normoalbuminuria from 


The two systematic reviews by Strippoli et al (2005) and Strippoli et al (2006) addressed the 

use of antihypertensive agents in people with diabetes with respect to renal outcomes. The 

objectives of the review by Strippoli et al (2005) were to evaluate the effects of 

antihypertensive agents in people with diabetes and normoalbuminuria. While the objectives 

of the review by Strippoli et al (2006) were to evaluate the benefits and harms of ACEi and 

ARBs in preventing the progression of CKD. Both reviews included studies of both type 1 

and type 2 diabetes and in the case of Strippoli et al (2006) people with either 

microalbuminuria or macroalbuminuria. Whilst the reviews included both type 1 and type 2 

diabetes the majority of selected trials enrolled only people with type 2 diabetes. 

The overall conclusions of the two systematic reviews are summarised below: 

• A significant reduction in the risk of developing microalbuminuria in normoalbuminuric 

patients has been demonstrated for ACEi only. This effect appears to be independent of 

blood pressure and, kidney function and type of diabetes. However, there is insufficient 

data to be confident that these factors are not important effects modifiers (Strippoli et al, 

2005). 

• There is randomised trial evidence that ACEi versus placebo/no treatment used at their 

maximum tolerable dose prevent death in people with diabetic kidney disease but not so 

for ARB versus placebo/no treatment. Both agents prevent progression of nephropathy 

and promote regression to a more favorable clinical pattern of normoalbuminuria. The 

relative effects of ACEi and ARBs are uncertain due to a lack of head to head trials 

(Strippoli et al, 2006). 

In relation to type 2 diabetes the following outcomes are of note from the reviews by 

Strippoli et al (2005) and Strippoli et al (2006): 

• All-cause mortality: 

- non significant effect of ACEi. vs. placebo. 

- comparison between ACEi and CCB – no significant difference, however only two 

studies were available where relative risk could be estimated. 

- at less than the maximum tolerable dose for ACEi vs. placebo/no treatment – no 

significant effect. 

- at the maximum tolerable dose for ACEi vs. placebo/no treatment – no significant 

effect in the two relevant studies both of which were mixed type 1 and type 2 diabetes 

populations. 

- for ARB vs. placebo/no treatment – all of the studies included people with type 2 

diabetes and no significant effect was noted. 

• Doubling of serum creatinine 

- non significant effect of ACEi vs. placebo. 

- comparison of ACEi and CCB – no available suitable studies where relative risk was 

able to be estimated. 

- for ACEi vs. placebo/no treatment – overall effect of marginal significance in favour 

of ACEi. 

- for ARB vs. placebo/no treatment – the two studies selected both included people 

with type 2 diabetes with an overall significant reduction for ARB compared to 

placebo/ no treatment. 


• Progression to ESKD 

- non significant effect of ACEi vs. placebo in the one mixed type 1/type 2 diabetes 

study only (The HOPE Study Group 2000). 

- comparison between ACEi and CCB - no available suitable studies where relative risk 

was able to be estimated. 

- for ACEi vs. placebo/no treatment – non significant relative risk in the two studies 

that included people with type 2 diabetes. 

- for ARB vs. placebo/no treatment – the two studies selected both included people 

with type 2 diabetes with an overall significant reduction in progression to ESKD for 

ARB compared to placebo/ no treatment. 

• Progression from normoalbuminuria to microalbuminuria or macroalbuminuria 

- overall significant effect of ACEi vs. placebo in reducing the rate of progression. 

- ACEi compared to other hypertensive agents – limited to the UKPDS study which 

showed no significant effect of ACEi in reducing the rate of progression. 

- normotensive patients - ACEi vs. placebo – no trials identified with people with type 

2 diabetes. 

- hypertensive patients - ACEi vs. placebo - evidence for significant reduction in rate of 

progression with ACEi treatment. 

- ACEi compared to CCB – significant effect of ACEi in reducing the rate of 

progression. 

• Progression of microalbuminuria to macroalbuminuria: 

- ACEi vs. placebo/no treatment – the type 2 diabetes studies are weighted to a relative 

risk less than one (i.e. favoring ACEi) consistent with the overall assessment of the 

studies with type 2 diabetes studies accounting for approximately 70% of the total 

number in all selected studies. 

- ARB vs. placebo/no treatment – all selected studies included people with type 2 

diabetes and show an overall reduction in the rate of progression in favour of ARB 

treatment. 

• Regression from microalbuminuria to normoalbuminuria 

- ACEi vs. placebo/no treatment – the type 2 diabetes studies are weighted to a relative 

risk greater than 1 (i.e. favors ACEi) consistent with the overall assessment of studies 

with type 2 diabetes being approximately 65% of the total number in all of the 

included studies. 

- ARB vs. placebo/no treatment – the two trials included people with type 2 diabetes 

and show an overall marginal increase in the rate of regression in favor of ARB 

treatment. 

• Comparison of effect on blood pressure: 

- ACEi vs. placebo no trials identified that included people with type 2 diabetes. 

- ACEi and CCB on blood pressure – no significant effect, however limited to one 

mixed type 1/type 2 diabetes study. 

The relevant trials comparing ACEi treatment with ARB treatment all included people with 

type 2 diabetes and no significant differences on all cause mortality, progression of 

microalbuminuria to macroalbuminuria or regression from microalbuminuria to 

normoalbuminuria were noted by Strippoli et al (2006). However, as noted in the overall 

conclusion by the authors the trials were limited and provide insufficient evidence for 

comparison of effects. 

The objectives of the systematic review by Kaiser et al (2003) was to assess the RCT 

evidence for the effects of different therapeutic blood pressure goals and interventions in the 

normotensive range on the decline of glomerular function. The search strategy was limited to 

studies of people with two years duration of type 1 or type 2 diabetes with incipient or overt 


nephropathy with or without elevated blood pressure. The intervention was required to be 

treatment with one or more hypertensive agents. The review identified 5 RCTs meeting the 

search criteria. All of these studies have been identified and assessed by Newman et al 

(2005), Strippoli et al (2005) and Strippoli et al (2006). Only two studies that considered the 

effect of BP targets within the normotensive range in people with type 2 diabetes were 

identified, namely Schrier et al (2002) and Estacio et al (2000). 

Kaiser et al (2003) considered GFR as surrogate endpoint in the absence of a renal failure 

endpoint such as need for dialysis and/or transplantation. The authors noted that no trial 

demonstrated any beneficial effect of lower target BP values on the progression of kidney 

failure. In short decreases in albuminuria were not accompanied by a decrease in the rate of 

decline in GFR. They conclude that the available evidence does not support a beneficial 

effect of BP lowering within the normotensive range on progression of diabetic nephropathy 

as assessed by the change in GFR. 

The systematic review and meta analysis by Jennings et al (2007) pooled analyses from the 

number of small studies comparing combination treatment of ACEi + ARB with ACEi alone. 

A total of ten studies covering both type 1 and type 2 diabetes were included in the metaanalysis. 

The majority of the studies were of people with type 2 diabetes. The authors 

concluded that the meta-analysis suggests that combined ACEi + ARB reduces 24 hour 

proteinuria to a greater extent than ACEi alone and that this benefit is associated with small 

effects on GFR. However, analysis also concludes that the available studies were 

heterogeneous and mostly of short duration (only one study greater than 12 weeks) and the 

few longer term studies have not demonstrated a benefit. 

Hamilton et al (2003) conducted a meta-analysis of RCTs evaluating the efficacy of ACEi in 

the treatment of nephropathy in individuals with type 2 diabetes. Specifically the metaanalysis 

addressed the reduction in albuminuria or proteinuria and thus included only those 

studies that provided either geometric or arithmetic means of albuminuria. Studies reporting 

geometric means and arithmetic means were analysed separately. The results of the metaanalysis 

indicated that treatment with ACEi produced significant reductions in albuminuria in 

people with type 2 diabetes in studies where geometric means were used to normalise data 

but less clear where data is reported as arithmetic means (presumed to reflect the skewing of 

the albuminuria data). Whilst studies were stratified on the basis of the degree of albuminuria 

and study duration, no distinction between normotensive or hypertensive patients have been 

made. 

Studies with ARB’s in people with type 2 diabetes and overt kidney disease have shown that 

angiotensin receptor blockade with irbesartan attenuates the rate of doubling of serum 

creatinine by 20-30% over 2.7 years when compared with placebo or amlodipine, used in 

equihypotensive doses (Brenner et al, 2001). A study of angiotensin receptor blockade with 

irbesartan in hypertensive, microalbuminuric people with type 2 diabetes showed a 70% 

decrease in AER over 2 years (Parving et al, 2001). However, preservation of GFR over and 

above the effects of blood pressure lowering was not demonstrated in this relatively shortterm 

study. 

Studies not covered by Systematic Reviews 

The ADVANCE study (ADVANCE 2007) is a multinational randomised control trial 

undertaken by 215 centres across 20 countries which, in addition to intensive blood glucose 

treatment, included a blood pressure treatment study arm. Participants were randomised to 

either fixed combined perindopril indapamide or placebo. Additional antihypertensive agents 


were allowed for both groups as required with the exception that thiazide diuretics were not 

allowed and the only open labeled ACEi allowed was perindopril to a maximum dose of 4mg 

a day thereby ensuring that the active treatment group did not exceed the maximum 

recommended dose. The active treatment resulted in a mean reduction after 4.3 years 

(median) in SBP and DBP of 5.6 and 2.2 mmHg respectively, compared to placebo. The 

relative risk of a major microvascular event was 7.9% in the active treatment group compared 

to 8.6% in the placebo group, however this was not significant. Active treatment was 

associated with a borderline significant reduction in macroalbuminuria and a significant 

reduction in the development of microalbuminuria with a relative risk reduction of 21% (95% 

CI 15-30). Further detailed analysis of the ADVANCE trial data (Galan et al, 2008) has 

indicated that lower achieved follow-up systolic blood pressure levels were associated with 

progressively lower renal event rates to below 110 mmHg. Renoprotective effects of blood 

pressuring lowering with perindopril indapamide treated were noted even among the sub 

group with baseline blood pressure below 120/70 mmHg. 

An open label parallel prospective randomised trial (Yasuda et al, 2005) provides a 

comparison of the effects of a ARB (losartan) and a CCB (amlidopine) on the UAE and ACR 

of 87 hypertensive type 2 diabetes Japanese patients with persistent macroalbuminuria. The 

ARB and CCB treatments provided similar blood pressure control (no significant difference). 

The ARB treatment resulted in a 30% drop in the UAE after 6 months treatment and a 16 % 

drop in the ACR. There was no significant change in both the UAE and the ACR in the CCB 

treatment. 

In relation to ACEi, a number of additional trials have been identified, the details and 

findings of which are summarized in Table 10 including, Jerums et al (2004), Marre et al 

(2004), Baba & -MIND Study Group (2001) and Fogari et al (2000) While the study by 

Lacourciere et al (2000) (also summarized in Table 10) has examined both ACEi and ARBs 

either alone of in combination. 

A number of studies have specifically assessed the ARB valsartan namely Estacio et al 

(2006), Galle et al (2008), Hollenberg et al (2007), SMART Group (2007), Tan (2002) and 

Viberti (2002). The details and findings of these studies are summarized in Table 10 below. 

Overall, the studies are consistent with the renoprotective effect of ARBs, however they do 

not provide additional data allowing a direct comparison with ACEi. 

The BENDICT Trial was a long term (median 43 months) prospective multicentre RCT of 

1204 people with type 2 diabetes, elevated blood pressure and normoalbuminuria 

(Ruggenenti et al 1998; Remuzzi et al 2006). The trial was aimed at assessing the efficacy of 

ACEi and CCB alone and in combination. Additional agents were permitted to achieve 

appropriate blood pressure control. Trandolapril plus verapamil and trandolapril alone 

decreased the incidence of microalbuminuria to similar extent. Verapamil alone was found to 

be no different to the placebo. 

The comparative effects of HCT, ACEi and ARB on UAE (as a secondary outcome) in the 

study by Schram et al (2005) were assessed in 70 people with type 2 diabetes in the 

Netherlands. The people with type 2 diabetes were Caucasian with an average age in the 

randomised treatment groups of 60 to 63, hypertensive and either normoalbuminuric or early 

microalbuminuric (UAE < 100 mg/d). The trial was of 12 months duration after a 1 month 

run in and a 4 to 6 month blood pressure titration period. All three agents achieved the 

aggressive BP goals equally well in the three treatment groups. The UAE was reduced by 

around 35% over 12 months and there was no significant difference between the three 

treatments. The authors note that this outcome may reflect the relatively small sample size. 

This additional ACEi/ARB comparative study from those reported by Strippoli et al (2006) 


does not provide additional evidence for the efficacy of ARB compared to ACEi in achieving 

regression of microalbuminuria. 

The multicentric CENTRO trial of 129 Italians with type 2 diabetes compared the ARB 

candesartan with the ACEi enalapril with albumin excretion rate as a secondary outcome. In 

the study by Rosei et al (2005) after 6 months treatment the ARB treatment group had a 

reduced albumin excretion rate and ACR, while the ACEi was higher. However, the 

baseline conditions differed between treatment groups and the majority of individuals were 

normoalbuminuric thus the relevance of the outcomes for individuals with microalbuminuria 

is questionable. 

The GEMINI trial involved 1235 people with type 2 diabetes with elevated blood pressure 

under either a ACEi or ARB hypertension treatment randomised for treatment with two 

different β-blockers (carvedilol and metoprolol) (Bakris et al, 2005). A post hoc analysis of 

differential effects of the β-blockers on the progression of albuminuria indicated a greater 

reduction in microalbuminuria for carvedilol compared to metoprolol. In those with 

normoalbuminuria fewer progressed to microalbuminuria on carvedilol. These effects were 

not related to BP. Multivariate analysis demonstrated only baseline urine ACR and treatment 

were significant predictors of changes in albuminuria. In a separate analysis the presence of 

metabolic syndrome at baseline corresponded with an OR of 2.68 (95% CI 1.36 to 5.30) over 

the duration of the study. 

The DETAIL study involved 250 people with type 2 diabetes with mild to moderate 

hypertension and eGFR >=70ml/min/1.73m2 from 6 European countries (Barnett et al, 2004). 

The study compared an ARB and an ACEi treatment over 5 years. After 5 years the 

difference in eGFR between the ARB and the ACEi was -3.1 ml/min/1.73 m 2 and was 

insignificant. The mean annual declines in eGFR were 3.7 ml/min/1.73 m 2 for the ARB and 

3.3 ml/min/1.73 m 2 for the ACEi. These results were considered by the authors to be similar 

to eGFR decline reported in the IRMA 2, IDNT, and RENAAL studies and compare to an 

expected untreated type 2 diabetes annual decline in the order of 10 ml/min/1.73 m 2 . 

Telmisartan was concluded to be not inferior to enalapril in providing long-term 

renoprotection. However, the results do not necessarily apply to more advanced nephropathy 

but support clinical equivalence of ARB and ACEi in persons with conditions that place them 

at high risk for CV events. 

The large ONTARGET trial comparing ARB and ACEi of in excess of 25,000 participants 

included a large proportion with diabetes and microalbuminuria (ONTARGET 2008). 

Relevant secondary outcomes are kidney impairment and kidney failure requiring dialysis. 

The only significant differences between treatments (ACEi, ARB and ACEi+ARB) was for 

increased kidney impairment in the combination therapy compared to the ACEi. Further 

analysis of renal outcomes (Mann et al, 2008), indicated a significantly higher increase in 

ACR in the ACEi treatment group compared to the ARB and ACEi+ARB (31% vs. 24 and 

21%). The risk of developing new microalbuminuria was not different between ACEi and 

ARB treatment groups, but was significantly lower in the combination treatment group. 

However, in contrast to albuminuria a greater rate of decline in eGFR was noted for the 

combination treatment group compared, thus the authors concluded that there was no 

evidence for a renal benefit with combination therapy even though proteinuria was improved. 

No subgroup analysis has been undertaken with respect to diabetes or albuminuria. 

The short term (6 month) reported by Parving et al (2008) examined the renoprotective 

effects in people with type 2 diabetes with albuminuria of treatment with a direct renin 

inhibitor (aliskiren) in addition to maximal treatment with an ARB (losartan). Treatment 


with 300 mg of aliskiren was demonstrated to reduce the ACR by 18% compared to the 

placebo group and to increase the number of people with an albuminuria reduction of greater 

than 50% over the treatment period. These effects were independent of changes in blood 

pressure and therefore considered to indicate renoprotective effects of the treatment. The 

rationale behind the trial was provision of further benefit by use of a direct renin inhibitor in 

addition to maximal use of a angiotensin II receptor antagonist. 

Table 10 provides a summary of studies that provide evidence in relation to use of 

antihypertensive agents in people with type 2 diabetes and the progression of CKD. Included 

in Table 10 are details of a number of studies conducted prior to 2000 that have not been 

discussed above that are provided as an overview of the collective evidence in relation to the 

role of blood control in the progression of CKD namely, Muirhead et al (1999), Ravid et al 

(1998a), Sano et al (1994) and Trevisan & Tiengo (1995). 


Table 10: Summary of studies relevant to the assessment of the role of blood pressure control and antihypertensive agents in CKD and 

individuals with type 2 diabetes. 

Study ID Study Description Intervention Outcome Relevant 

to CKD 

Follow 

up 

(mths) 

Comments 

ADVANCE 

(2007) and 

Galan et al 

(2008) 

Agardh et al 

(1996) 

Ahmad et al 

(1997) 

Baba & - 

MIND Study 

Group (2001) 

MIND 

RCT 

Multicentre (215 across 20 

countries) 

Type 2 diabetes diagnosed at 30 

years or older. Age >=55 years at 

the start of the study. History of 

major vascular or microvascular 

disease or at least one other risk 

factor for vascular disease. 

n=11,000 


Multicentre, multinational 

Type 2 diabetes, microalbuminuria, 

early diabetic neuropathy, 

hypertensive 

239 males 

96 females 

RCT single blind 

India 


Normotensive 

n=103 

RCT – intent to treat analysis 

Multicentre Japan 


Normoalbuminuria 

Microalbuminuria 

n=486 

Perindopril plus 

indapamide 

vs. 

placebo. 

Lisinopril vs. 

Nifedipine 

ACEi 

vs. 

Placebo 

ACEi 

vs. 

CCB 

Worsening 

nephropathy i.e. 

development of 

macroalbuminuria, 

doubling of serum 

creatinine, need for 

renal replacement 

therapy or death due 

to kidney disease. 

UAE, creatinine 

clearance 

52 

(median) 

Active treatment mean reduction in SBP and DBP of 5.6 and 2.2 mmHg 

respectively, compared to placebo. The relative risk of a major 

microvascular event was 7.9% in the active treatment group compared to 

8.6% in the placebo group (non significant). Active treatment was 

associated with a borderline significant reduction in macroalbuminuria 

and a significant reduction in the development of microalbuminuria with 

a relative risk reduction of 21% (95% CI 15-30). 

12 Significantly more beneficial effect on UAE, however creatinine 

clearance did not change significantly with either treatment. 

AER 60 After 5 years ACEi treated patients experienced significantly less 

progression of microalbuminuria to clinical albuminuria. 

UAE 24 CCB and ACEi had a similar effect on nephropathy in hypertensive 

people with type 2 diabetes without overt proteinuria. 



to CKD 

Follow 

up 

(mths) 

Comments 

Bakris et al 

(2005) 

GEMINI 

Barnett et al 

(2004) 

DETAIL 

Chan et al 

(2000) 

Estacio 

(2006) 

RCT 

Type 2 diabetes, hypertension, 

ACEi or ARB as part of the 

treatment regime prior to 

commencement of the study. 

n=1235 

RCT, double blind. 

Multicentre (39), 6 European 

countries 

Type 2 diabetes, mild to moderate 

hypertension, all had to have been 

treated by an ACEi to eliminate 

intolerance, GFR >70 ml/min per 

1.73 m 2 , mostly white and male. 

n=250 

RCT 


Hypertensive 

n=102 

RCT 

type 2 diabetes 

normotensive 

n=129 

Metoprolol 

(maintain 

ACEi/ARB) 

vs. 

Carvedilol 

(maintain 

ACEi/ARB) 

ARB (telisartan – 

40 mg/day up to 

80 mg/day for BP 

control) 

ACEi (enalapril – 

10 mg/day up to 

20 mg/day for BP 

control) 

(Additional 

hypertensive 

allowed as 

required) 

ACEi 

vs. 

CCB 

Intensive BP 

control (valsartan 

+ other as 

required) vs. 

Moderate BP 

control (placebo 

plus others as 

required) 

Albuminuria (spot 

ACR) 

GFR (calculated 

from serum 

creatinine), UAE 

UAE, CCr 

UAE, serum 

creatinine, 

creatinine clearance 

5 after 

reaching 

target BP 

Pre specified and post hoc analyses of the GEMINI trial. Greater 

reduction in microalbuminuria was observed for carvedilol. Those with 

normoalbuminuria fewer progressed to micro on carvedilol. This effect 

was not related to BP. Multivariate analysis in albuminuria change 

demonstrated only baseline urine ACR and treatment were significant 

predictors. In a separate analysis – the presence of metabolic syndrome 

at baseline corresponded with an OR of 2.68 (95% CI 1.36 to 5.30) over 

the duration of the study. 

60 The difference in GFR between the ARB and the ACEi was -3.1 

ml/min/1.73 m 2 and was insignificant. The mean annual declines in 

GFR were 3.7 ml/min/1.73 m 2 for the ARB and 3.3 ml/min/1.73 m 2 for 

the ACEi. These results similar to GFR decline reported in IRMA 2, 

IDNT, and RENAAL studies. Compare to untreated Type 2 diabetes 

annual decline of 10 ml/min/1.73 m 2 . 

Telmisartan is not inferior to enalapril in providing long-term 

renoprotection. Does not necessarily apply to more advanced 

nephropathy – but support clinical equivalence of ARB and ACEi in 

persons with conditions that place them at high risk for CV events. 

Initially 

12 then 

54 

(mean) 

23 

(median) 

Treatment with ACEi associated with greater reduction in albuminuria 

than with CCB in the entire patient group and especially in those with 

microalbuminuria. In macroalbuminuria, rate of deterioration in renal 

function was also attenuated with ACEi. 

Int BP – 118 ±10.9/75±5.7 

Mod BP – 124 ±109/80 ±6.5 

UAE – significant treatment difference at 2 years. 



to CKD 

Follow 

up 

(mths) 

Comments 

ABCD 

Estacio et al 

(2000) 

Estacio & 

Schrier (1998) 

Schrier et al 

(2002) 

RCT prospective 


Normotensive (DBP between 80 

and 89 mm/Hg, not receiving 

antihypertensives) 

n=470 

ACEi, enalpril 

vs. 

CCB, nisoldipine 

vs. 

Placebo 

Creatinine 

clearance, UAE 

64 Blood pressure control of 138/86 or 138/78 mm/Hg with either ACEi or 

CCB as the initial hypertensive agent appeared to stabilise renal function 

in hypertensive people with type 2 diabetes without overt albuminuria 

over a 5 year period. More intensive BP control decreased all cause 

mortality. Intensive BP control in normotensive Type 2 diabetes slowed 

progression to incipient and overt nephropathy, decreased progression of 

retinopathy and diminished the incidence of stroke. Study indicates BP 

control as being the important factor rather than ACEi vs. CCB. 

Fogari et al 

(2000) 

Galle et al 

(2008) 

VIVALDI 

Hollenberg et 

al (2007) 

RCT 

Type 2 diabetes (well controlled), 

60 to 75 years, hypertensive 

n=147 

RCT 

Multicentric 

Type 2 diabetes with hypertension, 

proteinuria and serum creatinine


to CKD 

Follow 

up 

(mths) 

Comments 

Jerums et al 

(2004) 

Lacourciere et 

al (1993) 

Lacourciere et 

al (2000) 

Lebovitz et al 

(1994) 

Marre et al 

(2004) 

DIABHYCA 

R 

RCT prospective open, blinded 

endpoint 


n=77 

RCT double blind 

Caucasian (45 to 75 years) 


Mild to moderate hypertension 

n=109 


Multicentre 

Canada 


Hypertensive 

Early nephropathy 

n=92 



Hypertensive 

n=121 

RCT double blind, parallel group 

Multicentre, primary care, 16 

European and North African 

Type 2 diabetes >50 years 

Persistent microalbuminuria or 

proteinuria 

ACEi 

CCB vs. 

Placebo 

ACEi vs. 

conventional 

therapy 

ACEi vs. 

ARB 

ACEi vs. 

Placebo 

ACEi (on top of 

usual treatment) 

vs. 

Placebo 

GFR, albuminuria 66 

(median) 

Long-term control of blood pressure with ACEi or CCB stabilises AER 

and attenuates GFR decline in proportion to MAP in non-hypertensive 

people with Type 2 diabetes and microalbuminuria. 

UAE 36 Treatment with captopril decreased albuminuria and reduced the 

development of macroalbuminuria in those with persistent 


Renal bioindicators 12 Treatment with either ACEi or ARB significantly reduced UAE. 

Reduction in UAE with each treatment was similarly related to 

decrements in ABP. Rate of decline in GFR was similar in both 

treatment groups. 

UAE, protein, urea, 

nitrogen, creatinine, 

GFR 

ESKD 

Secondary –UAE, 

urinary protein 

36 ACEi preserved GFR better in patients with sub-clinical proteinuria at 

baseline better than other antihypertensives without ACEi. Smaller 

percentage proceeded to clinical albuminuria. 

72 

(median) 

Low dose ramipril once daily has no effect on CVD and kidney 

outcomes (Type 2 diabetes and albuminuria) despite slight decrease in 

blood pressure and UAE. 

Muirhead et al 

(1999) 

n=4912 


Multicentre, Caucasian 

Type 2 diabetes, normotensive, 

microalbuminuria 

n=122 

ACEi 

ARB 

vs. 

Placebo 

UAE 12 The ARB slowed progressive rise of UAE compared to the ACEi. 



to CKD 

Follow 

up 

(mths) 

Comments 

Nakamura et 

al (2002) 

ONTARGET 


Mann et al 

(2008) 

RCT, 

Type 2 diabetes, normotensive, 


n=60 

RCT 

Heart disease, included 38% with 

diabetes (Type 1 and Type 2) and 

13% with microalbuminuria 

n=25,000 

ACEi 

ARB 

ACEi + ARB 

vs. 

Placebo 

ACEi (Ramipril) 

vs. 

ARB 

(Telmisartan) 

vs. 

Combination 

UAE 18 Data suggest the combination of ARB/ACEi has an additive effect. On 

the reduction of microalbuminuria. 

eGFR, UAE 

Secondary- 

Renal impairment 

(based on clinical 

investigators report) 

Renal failure 

requiring dialysis. 

56 

(median) 

No subgroup analysis has been presented including diabetes and 

microalbuminuria. Therefore not generaliseable to Type 2 diabetes. 

Overall, no significant differences noted between treatments except for 

renal impairment. Combination treatment resulted in lower ACR and 

lower onset of new microalbuminuria at the end of the follow up period, 

however greeter rate of decline in eGFR. 

Parving et al 


Brenner et al 

(2001) 


Multicentre, multinational 


n=1513 

ARB 150mg/day 

ARB 300 mg/day 

vs. 

Placebo (and 

conventional 

hypertensive 

treatment) 

Serum creatinine 

doubling, ESKD, 

death, proteinuria, 

progression of 

kidney disease 

40 

(mean) 

Losartan conferred significant renal benefits in Type 2 diabetes with 

neuropathy and was generally well tolerated. 



to CKD 

Follow 

up 

(mths) 

Comments 

Parving et al 

(2008) 

Ravid et al 

(1993) 

Ravid et al 

(1998a) 


controlled 

Multicentric, multinational 

Type 2 diabetes, nephropathy. 

Excluded - known non diabetic 

nephropathy, ACR > 3500 mg/g, 

eGFR < 30 ml/min, chronic UTI, 

severe hypertension, cardiovascular 

disease within the previous 6 

months. 

n=599 

RCT – double blind fist phase and 

open second phase. 

Israel, Multicentre 


Normotensive 


n=94 


Multicentre 


Normotensive 


n=156 

Aliskiren (direct 

renin inhibitor) 

150 mg for 3 

moths 

300 mg for 3 

months. 

vs. placebo 

Both – maximal 

losartan (100 mg) 

plus additional 

hypertensive to 

achieve optimal 

BP (i.e. target of 

130/80 mm Hg). 

ACEi 

vs. 

Placebo 

ACEi vs. 

Placebo 

Urinary ACR, 

eGFR. 

AER 


clearance 

6 After adjustment for changes from base line in systolic BP, the aliskiren 

treatment reduced the mean urinary ACR by 18% compared to the 

placebo. The treatment group had a greater number of patients where 

albuminuria reduction was greater than 50% (24.7% vs. 12.5%). 

60 – on 

treatment 

24 – 

choice 


treatment 

The benefit of aliskiren appeared to be independent of differences 

(small) in blood pressure. 

ACEi offers long term protection against the development of 

nephropathy in normotensive with microalbuminuria, and it stabilises 

renal function in previously untreated patients with impaired renal 

function. Discontinuation of treatment results in renewed progression of 

nephropathy. 

70 ACEi attenuated the decline in renal function and reduced the extent of 

albuminuria in normotensive, normoalbuminuric people with type 2 

diabetes. 



to CKD 

Follow 

up 

(mths) 

Comments 

Rosei et al 

(2005) 

CENTRO 

Ruggenenti et 

al (1998) also 

Remuzzi et al 

(2006) 

BENEDICT 

RCT 

Multicentre 


Mild hypertension, either 

previously untreated for 

hypertension or unsuccessfully 

treated. 

n=129 

RCT 

Multi centre 


Hypertension 


n=1204 

ACEi – enalapril 

(20 mg/d) vs. 

ARB – 

candesartan (16 

mg/d) 

(HCT used for 

additional 

treatment as 

required.) 

- Verapamil – 240 

mg/day 

- Tradolapril – 2 

mg/day 

- Verapamil plus 

trandolapril 

vs. 

Placebo 

UAE 6 Candestartan and enalapril showed similar effects on BP and circulating 

adhesion molecules. UAE was reduced significantly more by 

candestartan. However, the majority of patients had normal protein 

excretion and therefore difficult to extrapolate the results obtained. 

UAE 43.2 Additional agents permitted to achieve BP control. 

Trandolapril plus verapamil and trandolapril alone decreased incidence 

of microalbuminuria to similar extent. Verapamil alone no different to 

placebo. 

Sano et al 

(1996) 


Japan 


Normotensive 


n=62 

ACEi 

vs. 

No treatment 


clearance 

48 UAE in treated group decreased and increased slowly in untreated group. 



to CKD 

Follow 

up 

(mths) 

Comments 

Schram et al 

(2005) 

SMART 

Group (2007) 

Tan et al 

(2002) 

The HOPE 

Study Group 

(2000) 

Trevisan & 

Tiengo (1995) 

UKPDS 

(1998b) 

Efficacy of 

ACEi vs. beta 

RCT, double blind, double dummy 

Multi-centre, The Netherlands, 

Caucasian. 

Type 2 diabetes, Hypertensive, 

mean age in treatments 60 to 63, 

UAE < 100 mg/d (normo and 

microalbuminuric) 

n=70 

RCT 

Type 2 diabetes with 


n=341 




n=80 

RCT 

Multicentre 

CVD or diabetes plus high CVD 

risk. (98% Type 2 diabetes) 

n=3577 


Italy – multicentre 



Normal or mild hypertension 

n=122 

RCT 

Multicentre UK 20 hospital clinics 


Hypertensive 

n=1148 

HCT – 12.5 mg/d 

ACEi – 10 mg/d 

ARB – 8 mg/d 

vs. 

Dummy placebos 

used to maintain 

double blind. 

Valsartan 

vs.amlodipine 

ARB vs. 

Placebo 

Ramipril vs. 

Placebo 

ACEi 

vs. 

Placebo 

ACEi vs. 

Beta blocker 

UAE (secondary 

outcome) 

1 run in 

4 to 6 

titration 

period 

12 study 

There was no significant difference in the UAE between the treatment 

groups, which may be a consequence of the small sample size. 

Aggressive antihypertensive therapy can improve UAE in hypertensive 

people with type 2 diabetes regardless of the type of therapy used. 

ACR 3 Valsartan – ACR 68% of baseline 

Amlodipine – ACR 118% of baseline 

Remission – 23 vs. 11% 

Regression – 34 vs. 16% 

UAE 6 People with type 2 diabetes and microalbuminuria have impaired 

endothelium-dependent and –independent vasodilatation. Treatment 

with low dose losartan is sufficient to reduce microalbuminuria without 

alteration in endothelial function and systemic blood pressure. 

Albuminuria 

(secondary 

outcome) 

54 Significant reduction in risk of overt nephropathy in ramipril treatment 

group. No difference in risk of new microalbuminuria. 

AER 6 Low dose ACEi can arrest the progressive rise in albuminuria in Type 2 

diabetes with persistent microalbuminuria. 

UAE 100 

(median) 

BP lowering with captopril was similarly effective in reducing the 

incidence of diabetic complications. 



to CKD 

Follow 

up 

(mths) 

Comments 

UKPDS 

(1998d) 

Tight blood 

pressure 

control 

RCT 

Multicentre UK 20 hospital clinics 


Hypertensive 

n=1148 

ACEi vs. 

Beta blocker 

Diabetes related 

deaths and all cause 

mortality. 

UAE 

100 

(median) 

Tight blood pressure control in patients with hypertension and type 2 

diabetes achieves a clinically important reduction in the risk of deaths 

related to diabetes, complications related to diabetes, progression of 

diabetic retinopathy, and deterioration in visual acuity 

Viberti (2002) 

MARVAL 

Yasuda et al 

(2005) 

RCT 

Type 2 diabetes with 


n=332 

Open-label parallel prospective 

RCT 

Japan 

Type 2 diabetes, Overt nephropathy 

(UAE between 300 and 3000 

mg/day), 31 and 80 years (average 

44), hypertensive 

n=87 

Valsartan vs. 

amlodipine 

(additional agents 

used to meet BP 

target of 135/80 

mm/Hg) 

ARB – losartan 

25 up to 100 mg/d 

CCB – 

amlodipine 2.5 up 

to 10 mg/d 

AER 6 More patients reverted to normoalbuminuria with losartan 29.9% vs. 

14.5%). BP reductions were similar. 

UAE, ACR 6 ARB – UAE reduced from 810 mg/day to 570 mg/day (P

iii) 

Role of Blood Lipid Modification 

• The extent to which interventions with lipid lowering therapy reduces the 

development of CKD is unclear (Evidence Level I – Intervention). 

As detailed below there are some trials that show that, over and above the cardio-protective 

actions, lipid-lowering may also exert beneficial effects on the development and progression 

of kidney disease in individuals with type 2 diabetes, as determined by albuminuria and/or 

GFR. However, there are no RCT studies in which renal outcomes including ESKD or 

doubling of serum creatinine have been used. It is unlikely that these studies will ever be 

performed given the overwhelming benefit of lipid lowering in terms of cardio-protection. 

Clinical trials in cardiovascular disease studying agents targeting dyslipidaemia have 

commonly excluded subjects with late stage chronic kidney disease. Moreover, the 

significant cardiovascular benefits of these agents could confound associations between lipid 

effects and renal function outcomes. Consequently, conclusions regarding their potential as 

reno-protective agents must be limited by reliance on early, surrogate markers of kidney 

disease and its progression. 

An overall summary of relevant studies is provided in Table 11 with findings from key 

studies described in the text below. 

Systematic reviews and meta-analyses: 

Sandhu et al (2006) conducted a systematic review and meta-analysis to determine the effect 

of statins on the rate of kidney function loss and proteinuria in individuals with CKD (with 

and without diabetes). They included 27 eligible studies with 39,704 participants (21 with 

data for eGFR and 20 for proteinuria or albuminuria). Overall, the change in the eGFR was 

slower in statin recipients (by approximately 1.2 ml/min/year). In addition, treatment with 

statins resulted in a significant reduction in baseline albuminuria and/or proteinuria. 

However, the magnitude of cholesterol reduction from baseline was not significantly 

associated with the described renal benefit of statins in meta-regression. In the smaller studies 

specifically performed in people with type 2 diabetes and kidney disease (n=3) the change in 

eGFR was unaffected by statins, although the modest magnitude of the effect observed in the 

other (larger) trials, if translated to these smaller studies, would mean the latter were 

underpowered to detect an eGFR difference. 

Keating and Croom (2007) specifically addressed the pharmacological properties of and 

efficacy of the fibric acid derivative, fenofibrate, in the treatment of dyslipidaemia in 

individuals with type 2 diabetes. The review included consideration of effects on 

albuminuria in the two major RCTs (FIELD and DAIS, see below). In both trials fenofibrate, 

reduced the rate of progression from normoalbuminuria to microalbuminuria and 

microalbuminuria to macroalbuminuria and increased the rate of regression, when compared 

to treatment with placebo. This effect was modest in size. For example, the proportion of 

people developing microalbuminuria was significantly reduced in the FIELD trial (10% 

compared to 11%) and in the DAIS trial (8% compared to 18%). 

Strippoli et al (2008) examined data on 50 trials (30 144 people), 15 of which evaluated the 

potential renoprotective effect of statins. Most of these studies enrolled people with early or 

late stages of chronic kidney disease and with a history of coronary heart disease. These 

studies did not include people with moderate chronic kidney disease but without known 


cardiovascular disease. In the small number of studies reporting urinary protein excretion 

(g/24 h) in individuals with chronic kidney disease (6 randomised controlled trials, 311 

people;), statins modestly reduced albuminuria and/or proteinuria. However, in contrast to 

findings of other meta-analyses, no significant effect was observed on creatinine clearance 

(11 randomised controlled trials, 548 people). This review was unable to distinguish a 

specific response in individuals with diabetes. 

Fried et al (2001) conducted a meta-analysis of trials of effects of lipid lowering therapy on 

nephropathy. A total 12 trials were included following systematic review, with all but one 

being a RCT. Of the 12 trials, the cause of kidney disease was stated as being due to diabetes 

(no distinction between type 1 or type 2 diabetes) in 7 of the 12 trials. Meta-analysis 

indicated that lipid reduction had a beneficial effect on the decline in GFR. The reduction in 

GFR from lipid-lowering therapy was 1.9 ml/min/year. There was no significant 

heterogeneity and no indication of publication bias. Regression analysis showed no 

relationship between effect of treatment and age, gender, cause of kidney disease and the type 

of lipid lowering therapy. No clear conclusions were possible with respect to effect of lipid 

lowering therapy on proteinuria due to significant heterogeneity. Overall the authors 

concluded that meta-analysis suggests that lipid lowering therapy may help slow the rate of 

kidney disease progression. However, the applicability to type 2 diabetes is less clear as no 

sub group analysis was conducted. 

Randomised clinical trials using statins 

Statins are the most widely used class of drug for lipid lowering in individuals with type 2 

diabetes. Currently in Australian practice at least two thirds of patients seeing their GP are 

receiving a statin. This reflects the clear and incontrovertible evidence that lowering of LDL 

cholesterol in individuals with type 2 diabetes is associated with reduced cardiovascular 

events and mortality (Costa et al, 2006). Moreover, when results were adjusted for baseline 

risk, people with diabetes benefited more in both primary and secondary prevention. In 

addition, a number of studies have looked at the effects of statins on renal parameters, 

including GFR, creatinine clearance and urinary albumin excretion. However, no trials report 

endpoints such as end stage kidney disease or doubling of creatinine as an outcome. The 

following trials provide evidence in relation to the use of statins in people with type 2 

diabetes and that also include renal outcomes. 

A number of major statin trials have been conducted, which have included individuals with 

type 2 diabetes. In post hoc analyses of these large studies, beneficial effects on renal 

functional parameters have been examined in the subgroup of participants with diabetes. 

• In the MRC/BHF heart protection study (HPS) (The Heart Protection Study 2003) 

subgroup analysis for participants with diabetes, allocation to simvastatin (40 mg/day) 

significantly decreased the rise in SCr values. Subjects were excluded from entering the 

trial if their serum creatinine was above 200 µmol/L, reflecting that those with late stage 

chronic kidney disease were not studied. 

• In the Greek atorvastatin and coronary heart disease evaluation (GREACE) substudy 

(Athyros et al, 2004) treatment with atorvastatin was associated with a significant 

decrease in urinary albumin excretion, however the study did not include separate 

analysis for type 2 diabetes. 

• The Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) 

(Koren 2005) study showed beneficial effects on GFR in individuals with type diabetes, 

however the study did not separately identify or assess type 2 diabetes. 


There have also been a number of studies examining the effects of statins on albuminuria and 

or creatinine clearance in individuals with type 2 diabetes, however most of these are small 

(i.e. less than 50). The following two studies have been identified: 

• A multicentric double blind parallel group RCT of type 2 diabetes Swedish patients with 

dyslipidaemia (fasting LDL-C > 3.3 mmol/L) compared two statin treatments 

(rosuvastatin and atorvastatin) over a 16 week treatment period (Sorof et al, 2006). The 

primary endpoints were UAE and GFR which were measured/calculated at baseline and 

at 8 and 16 weeks into the treatment period. The treatment goal (achieved by titration) 

was an LDL-C

the overall differences were relatively small (in the order of 2%). Albuminuria was a 

secondary outcome of the study. 

In the only study to compare statins and fibrates, head to head, in 71 individuals with type 2 

diabetes both benzafibrate and pravastatin prevented increase in the urinary albumin 

excretion rate over 4 years, with no difference observed between drug classes (Nagai et al, 

2000). 

Randomised clinical trials using other lipid lowering agents 

A number of other agents have clinically useful effects on dyslipidaemia in individuals with 

type 2 diabetes, including probucol and glitazones. However, their other primary actions, on 

oxidative stress and glucose lowering make it impossible to gauge the contribution of lipid 

lowering to their efficacy. Currently available glitazones do vary in their impact on lipid 

profiles, indicating sub-class variations in effect. Nonetheless, both agents appear to have 

effects on the development and progression of kidney disease in individuals with type 2 

diabetes 

The effects of probucol treatment on the progression of diabetic nephropathy was evaluated 

in a randomised open study of 102 people with type 2 diabetes with clinical albuminuria 

(UAE > 300 mg/g Cr) (Endo et al, 2006). The mean follow up period was 28.5 months for all 

patients and 18.6 months for advanced patients (defined as those having serum Cr > 2.0 

mg/dL). The mean interval to initiation of haemodialysis was significantly longer in 

probucol patients. In advanced cases treated with probucol, increases in serum creatinine and 

urinary protein were significantly suppressed and the haemodialysis-free rate was 

significantly higher. The study concluded that probucol may suppress the progression of 

diabetic nephropathy as a consequence of the antioxidative effect of the drug. 

The multifactorial intensive treatment of the STENO2 study (Gaede et al 2003b) reduced the 

risk of nephropathy by 50%. This long term study (mean 7.8 years) of 160 people with type 

2 diabetes and microalbuminuria, utilized multifactorial interventions for modifiable risk 

factors for cardiovascular disease which included blood lipid control with statins and fibrates. 

Whilst the intensive treatment group achieved a significantly lower blood glucose 

concentration, given the multifactorial nature of the study it is not possible to determine the 

relative contribution of the intensive lipid treatment may have had on the renal outcomes. 


Table 11: 

Summary of studies relevant to the role of blood lipid profiles in CKD in individuals with type 2 diabetes 



Ansquer et 

al (2005) 

DAIS – sub 

group 

analysis 

Endo et al 

(2006) 

Gaede et al 

(2003b) 

Steno2 

RCT 

11 Centres located in Canada, 

Finland, France and Sweden 

Type 2 diabetes (40 to 65 years), 

normo or microalbuminuria, 

adequate glucose control, mild to 

moderate lipid abnormalities. 

n=314 

RCT, open study, Single centre, 

Japan 

Type 2 diabetes, clinical albuminuria 

(UAE >300 mg/g Cr). 102 defined 

as advanced patients on the basis of 

serum Cr >2.0 mg/dL. 

n=102 

RCT 


n=160 

Fenofibrate 

vs. 

Placebo 

Probucol (500 

mg/day). Protein 

restriction diet. 

Blood glucose 

control to HbA1c 

(



Keech et al 

(2005) 

Radermecke 

r & Scheen 

(2005) 

FIELD 

RCT 

Multicentre, multi country 

Type 2 diabetes, not taking statin 

therapy. 

n=9 795 

Fenofibrate 

vs. 

Placebo 

Follow 

up 

(mths) 

UAE 60 

(average) 


Rate of progression to albuminuria was significantly reduced by 

fenofibrate and rate of regression was significantly increased. However, 

the differences in terms of numbers of patients was small (in the order of 

2%). 

Nagai et al 

(2000) 

Nakamura et 

al (2001) 

Nishimura et 

al (2001) 

Sorof et al 

(2006) 

The Heart 

Protection 

Study (2003) 

RCT 


n=71 


Type 2 diabetes, microalbuminuria, 

dyslipidaemia 

n=60 

RCT 

Multicentre, Japan 

Type 2 diabetes, normo and 

microalbuminuric 

n=168 

RCT, double blind, parallel group 

Multicentre, Sweden 

Type 2 diabetes, dyslipidaemia 

(fasting LDL-C > 3.3mmol/L) >18 

years (actual 65 years average), 

exclusions included - nephrotic 

syndrome, severe renal dysfunction, 

uncontrolled hypertension. 

n=344 

RCT 

Multicentre, UK 

Type 1 diabetes (10%) and Type 2 

diabetes (90%) 

5963 – Diabetes 

11307 – No diabetes 

Benzafibrate 

vs. 

Pravastatin 

Cerivastatin 

vs. 

Placebo 

ACEi 

Probucol 

vs. 

Placebo 

Rosuvastatin - 10 

mg with titration 

up to 40 mg 

vs. 

Atorvastatin – 10 

mg with possible 

titration to 80 mg 

Simvastatin (40 

mg/day) 

vs. 

Placebo 

UAE 48 UAE – no significant change over the 48 months with either drug. 

Conclude useful in preventative treatment of albuminuria and lipid 

lowering. 

UAE 6 BP, HbAc1 not significantly affected. Total chl and LDL chl reduced and 

concomitant decrease in UAE. 

UAE 24 ACEi has a beneficial effect and probucol may have a beneficial effect in 

preventing the progression of early diabetic nephropathy. 

UAE, GFR 

Plasma creatinine, 

eGFR 

(retrospectively) 

6 week 

run in 

4 month 

treatment 

. 

No change from baseline UAE for either treatment group, no significant 

change in GFR for either treatment group. 

60 Allocation to simvastatin was associated with a significantly smaller fall 

in eGFR over the trial period (5.9 ml/min vs. 6.7 ml/min) and was 

slightly larger amongst those with diabetes. 


iv) 

Role of Diet Modification 

• There are insufficient studies of suitable quality to enable dietary 

recommendations to be made with respect to CKD in people with type 2 

diabetes (Evidence Level II – Intervention). 

Lifestyle modification (diet and physical activity) is an integral component of diabetes care 

(refer to the guidelines for Blood Glucose Control in Type 2 diabetes). However, there are 

few studies that have specifically addressed kidney related outcomes in type 2 diabetes and as 

such it is not possible to currently make recommendations specific to the management of 

CKD. The following sections summarise the current evidence in relation to alternate diets, 

protein restriction, and salt. 

Role of Dietary Fats 

The Diabetes and Nutrition Clinical Trial (DCNT) is a population based prospective, 

observational multicentre study designed to evaluate the nutritional pattern of people with 

diabetes in Spain and associations with diabetic complications (Cardenas et al, 2004). The 

study (total 192) included a mix of people with type 2 diabetes (99) and type 1 diabetes (93). 

Nephropathy progression was indicated by change from normoalbuminuria to 

microalbuminuria and microalbuminuria to macroalbuminuria. Regression was indicated by 

change from microalbuminuria to normoalbuminuria. The nutritional pattern of people with 

nephropathy regression was characterised by greater polyunsaturated fatty acid (PUFA) and 

smaller saturated fatty acid (SFA) than those with nephropathy, whereas the PUFA to SFA 

and monounsaturated fatty acid (MUFA) to SFA ratios were greater. An opposite pattern 

was observed for progression of nephropathy. 

The authors note that the findings of the study are consistent with CVD studies and the role 

that SFAs may play in insulin sensitivity and other factors affecting diabetes control. 

Nonetheless, the authors consider that control of blood pressure and blood glucose and 

cessation of smoking should remain the therapeutic objectives for modifiable risk factors. 

When these objectives are obtained, other measures such as encouraging PUFA and MIFA 

over SFA may help prevent micro and macroalbuminuria (Cardenas et al, 2004). 

Table 12 presents a summary of the relevant studies found by the search strategy (Appendix 

3) in relation to dietary fat. With the exception of the study by Cardenas et al (2004) 

discussed above, the studies are either of short duration and thus provide little useful 

evidence for the role of dietary fat in the progression of CKD. Relevant details of the studies 

are provided in Table 12. In summary, there are insufficient reliable studies to support a 

recommendation in relation to the prevention and management of CKD in people with type 2 

diabetes. 

Type 2 Diabetes Guideline 82 Kidney Disease, June 2009

Table 12: 

Summary of studies relevant to the assessment of the role of dietary fat 



Barnard et al 

(2006) 

Cardenas et 

al (2004) 

Nicholson et 

al (1999) 

Nielsen et al 

(1995) 

Shimizu et 

al (1995) 

RCT 


n=99 

Prospective cohort 

Population based, multicentre 

Type 1 diabetes, Type 2 diabetes 

n=192 

RCT 


n=11 

Before and after cross over. Pseudo 

randomised trial. 

Type 2 diabetes, persistent 


n=10 

Before and after non randomised 

trial. Comparative study using 

patients grouped according to 

albuminuric status. 


n=115 

Low Fat Vegan 

vs. 

ADA diet 

Low fat vegan 

vs. 

Conventional low 

fat 

Diet rich in MUF 

vs. 

Recommended 

high carbohydrate 

diet 

Eicosapentaenoic 

acid ethyl (EPA- 

E) (present in cod 

liver oil) 

Follow 

up 

(mths) 


UAE 5 UAE greater reduction in vegan diet. Also improved glycaemic and lipid 

control. 

ACR 84 Normoalbuminuria and nephropathy regression in well-controlled 

diabetes in people with long term diabetes duration are associated with 

greater PUFA consumption and lesser SFA consumption, specifically 

higher PUFA/SFA and MUFA/SFA ratios – the opposite pattern is 

associated with progression of neuropathy. 

UAE 3 No significant effect on UAE. 

UAE 3 week No effect on UAE. However a potential beneficial effect on LDL/HDL 

ratio was detected. 

ACR 12 Improved increased albumin excretion in Type 2 diabetes with 

nephropathy and the effects were sustained at least 12 months after the 

start of treatment. 


Protein Restriction 

Intake of protein in the usual range does not appear to be associated with the development of 

CKD. However, long term effects of consuming >20% of energy as protein on development 

of CKD has not been determined. Although diets high in protein and low in carbohydrate 

may produce short-term weight loss and improved glycaemic control, it has not been 

established that weight loss is maintained in the long-term. There have been few prospective 

controlled studies of low protein diets in people with type 2 diabetes and kidney disease. The 

studies that have been performed have generally been deficient in experimental design, in 

methods for measuring kidney function and/or in duration of follow-up. Furthermore, the 

level of compliance with a low protein diet has not always been assessed objectively by 

urinary urea nitrogen excretion. A particular criticism is that changes in the creatinine pool 

and creatinine intake seen in low protein diet studies render measurements of creatinine 

clearance or the reciprocal of serum creatinine unreliable for the assessment of GFR 

(Shemesh et al, 1985). 

The objective of the systematic review by Robertson et al (2007) was to assess the effects of 

dietary protein restriction on the progression of diabetic nephropathy in people with diabetes 

(type 1 and type 2 diabetes). The review identified 11 studies (9 RCTs and 2 before and after 

trials) where diet modifications were followed for at least 4 months. Before and after trials 

were included as it was considered that people could act as their own controls. Of these 

studies 8 were of people with type 1 diabetes, one type 2 diabetes and two included both type 

1 and type 2 diabetes. Overall the total number of participants in the trials were 585 with 263 

being people with type 2 diabetes. Protein modified diets of all types lasting a minimum of 4 

months were considered with protein intake ranging from 0.3 to 0.8 g/kg/day. 

Overall protein restriction appeared to slow progression of CKD, but not by much on 

average. Individual variability suggests some may benefit more than others. Results of meta 

analysis implies that patients can delay dialysis by, on average around one or two months. 

Positive but non significant correlation between improvement in GFR and level of protein 

restriction is evident. There were insufficient studies to recommend a level of protein intake. 

Furthermore, problems of non compliance remain a significant issue. The review also 

considered different sources of protein (e.g. red meat, chicken, fish, vegetarian), however 

relevant studies are of short duration only. The authors consider that the available 

information supports further research in this area. The number of studies that include people 

with type 2 diabetes are limited. 

The study by Dussol et al (2005) was the only other RCT identified that was not reviewed by 

Robertson et al (2007). This 2 year single centre RCT of type 1 and type 2 diabetes indicated 

that the low-protein diet did not alter the course of GFR or of AER in people with diabetes 

with incipient or overt nephropathy. 

Table 13 includes a summary of studies identified by the search strategy (Appendix 3). The 

studies are characterised by being small and of short duration. Relevant details are provided 

below, however as for dietary fat, there are insufficient reliable studies that provide evidence 

to support a recommendation in relation protein restriction in the prevention and management 

of CKD in people with type 2 diabetes. 


Table 13: 

Summary of studies relevant to the assessment of the role of protein restriction 

Study ID Study Design Intervention Outcome 


Barsotti et al 

(1998) 

de Mello et 

al (2006) 

RCT 

Type 1 diabetes, Type 2 diabetes 

with chronic renal failure 

n=32 

Before and after – random order of 

diet Crossover 

Type 2 diabetes, macroalbuminuric 

n=17 

Low protein diet 

vs. 

Free 

Chicken (CD) 

Lactovegetarian 

Low Protein 

(LPD) vs. 

Usual (UD) 

Residual renal 

function 

GFR, UAE 

Follow 

up 

(mths) 

62.4 

(median) 

4 wk for 

each diet 


Study confirms the protective effect of low protein diets on nephropathy 

in the absence of any sign of protein malnutrition. 

Withdrawing red meat from diet reduces UAE rate. 

Dussol et al 

(2005) 

Gross et al 

(2002) 

Meloni et al 

(2004) 

Pijls et al 

(1999) 

RCT (unblinded) 

Single centre 

Type 1 diabetes and Type 2 diabetes 

Incipient or overt nephropathy and 

mild renal failure, 

Strict BP control using ACEi or ARB 

n=63 

RCT, cross over 

Type 2 diabetes, normo or 


n=28 

RCT, prospective 

Nephrology out patients, 80 with 

DKD (24 Type 1 diabetes, 56 Type 

2 diabetes) 

n=169 

RCT 


n=121 

Low protein 

vs. 

Usual protein 

(provided not 

greater than 1.2 

g/kg/day) 

Low protein 

Chicken (no red 

meat) 

vs. 

Usual diet 

Low protein diet 

vs. 

Free protein diet 

Counseling on 

protein restriction 

vs. 

Usual advice 

GFR, UAE 24 The low protein diet did not alter the course of GFR or UAE. The 

impact of a low protein diet in preventing the progression of diabetic 

nephropathy, if any, is small. 

GFR, UAE 1/1 with 1 

washout 

between 

Normoalbuminuric – both LP and chicken reduced UAE compared to 

normal diet. 

Microalbuminuric – only chicken reduced UAE compared to normal 

diet 

Renal function 12 Significant slowing of the progression of kidney damage was only 

observed in non diabetics. 

UAE 6 and 12 At 6 months experimental group had significantly. lower protein intake 

and significantly. lower UAE. At 12 months differences between 

groups had decreased. 




Pijls et al 

(2002) 

Pomerleau et 

al (1993) 

Teixeira et 

al (2004) 

Wheeler et 

al (2002) 

RCT 


n=131 


Type 2 diabetes, normotensive 

n=12 

Before and after cross over. Random 

order of interventions 


n=14 


Type 2 diabetes, microalbuminuric 

n=17 

Dietary 

counseling – 

protein restriction 

vs. 

Usual dietary 

advice 

3 week moderate 

protein 

vs. 

3 week high 

protein 

Isolated soy 

protein 

vs. 

Casein 

Plant based 

protein 

vs. 

Animal based 

protein 

Follow 

up 

(mths) 


GFR, UAE 28 +/- 7 Protein intake between groups at follow at 6 months differed by only 

0.08 g/kg/day. No differences by end of trial. Within the intervention 

group individuals with reduction of at least 0.2 mg/kg/day protein 

compared to controls with no change – showed non significantly 

difference in GFR. Conclude that protein restriction is neither feasible 

or efficacious. 

UAE, GFR, 

creatinine clearance 

3 week/ 3 

week 

Moderate diet reduced the UAE, GFR, proteinuria and creatinine 

clearance without adversely affecting glycaemic control. High protein 

diet induced small changes in renal function. 

UAE 2/2 with 1 

lead in 

and wash 

out 

UAE significantly reduced in ISP compared to casein. 

GFR, UAE 1.5/1.5 No significant difference between GFR and UAE. 


Restricted Salt Intake 

When considering the evidence related to salt intake and CKD in people with type 2 diabetes, 

the following points made by Suckling et al (2007) authors based on a literature review for 

preparation of a Cochrane Protocol are noteworthy: 

• Dietary salt is important in blood pressure control in both hypertensives and 

normotensives (supported by meta-analyses) and therefore expect that this could be 

protective in the development and progression of CKD. 

• High dietary salt suppresses the renin-angiotensin system (RAS). Salt sensitivity in 

people with diabetes may be increased due to less responsive RAS. Low salt intake 

enhances and high salt intake reduces the antiproteinuric effect of ACE inhibition. 

• Urinary albumin excretion is reduced by lowering dietary salt. 

• Changes in dietary salt may have a beneficial influence on TGF β production, affecting 

the progression of CKD. 

Table 14 presents a summary of studies identified by the search strategy (Appendix 3) in 

relation to the assessment of the role of restricted salt intake. As for protein restriction the 

studies are small and of short duration. Details of the studies are included in Table 14, 

however it is concluded that there are insufficient reliable studies that provide evidence to 

support a recommendation in relation to restriction of dietary salt and the prevention and 

management of CKD in people with type 2 diabetes. 

Type 2 Diabetes Guideline 87 Kidney Disease, June 2009

Table 14: 

Summary of studies relevant to the assessment of the role of restricted salt intake 



Houlihan et 

al (2000a) 

Houlihan et 

al (2002a) 

Houlihan et 

al (2002b) 

Imanishi et 

al (2001) 

Vedovato et 

al (2004) 

Yoshioka et 

al (1998) 

RCT – w.r.t losartan and placebo 

Type 2 diabetes, hypertensive, 


n=17 

RCT 

Type 2 diabetes, UAE 10-200 

µg/day, hypertension 

n=21 

RCT 

Type 2 diabetes, UAE 10-200 µg/day 

n=20 

Before and after cross over 

Type 2 diabetes – normo to 

macroalbuminuria, normal levels of 

serum creatinine 

n=32 

Before and after 


Case – microalbuminuria 

Control – normoalbuminuria 

n=42 

Cross over randomisation is limited 

to the order of diet 

Type 2 diabetes, normo to 

macroalbuminuria. 

n=19 

Low sodium 

vs. 

Normal sodium 

Losartan + low 

and high salt 

vs. 

Placebo + low and 

high salt 

Losartan + low 

and high salt 

vs. 

Placebo + low and 

high salt 

Sodium restricted 

diet 

vs. 

Normal sodium 

diet. 

Reduced salt 

vs. 

High salt 

Sodium restricted 

diet 

vs. 

Normal sodium 

diet. 

Follow 

up 

(mths) 


UAE 1/1 Low salt amplified both anti-hypertensive and anti-proteinuric effects of 

losartan and no significant effect in the placebo. 

TGF-beta (urine), 

UAE 

1/1 The ARB not sodium restriction reduced urinary TGF-beta 

ACR 1/1 ACR in losartan group decreased significantly with low salt. No 

significantly changes in placebo group. Demonstrated a low-sodium diet 

potentiates the antihypertensive and antiproteinuric effects of losartan. 

UAE 

1 week/ 

1 week 

UAE 1 week High salt increased BP and UAE 

Calculated IgG and 

albumin fractional 

clearances. 

1 week/ 

1 week 

Sodium sensitivity of blood pressure appears before hypertension and is 

related to albuminuria. 

Charge selectivity is lost before size selectivity as diabetic nephropathy 

progresses. 


v) Role of Smoking Cessation 

• Smoking increases the risk of the development and progression of CKD in 

people with type 2 diabetes (Evidence Level II – Aetiology). 

Interventional studies to assess the effects of smoking cessation have not been performed, but 

it has been calculated from the cause-specific 10-year mortality data of the subjects screened 

for the Multiple Risk Factor Intervention Trial (MRFIT), that stopping smoking is the most 

(cost-) effective risk factor intervention in people with diabetes. Smoking cessation would 

prolong life by a mean of 4 years in a 45-year old man and by 3 years in a diabetic man, 

whereas aspirin and antihypertensive treatment would provide approximately 1 year of 

additional life expectancy (Muhlhauser 1994; Yudkin 1993). The following cohort studies 

summarized in the text below and in Table 15, have included assessment of renal outcomes. 

Smoking has been found to be an independent risk factor for progression of AER in people 

with type 2 diabetes. In a prospective 9-year follow-up study of 108 people with type 2 

diabetes and normal AER after a duration of diabetes of 9 years, there was an overrepresentation 

of smokers (55% vs. 27%; p=0.01) in people who progressed to micro- or 

macroalbuminuria vs. those who did not progress (Forsblom et al, 1998). 

A number of prospective cohort studies were identified by the search strategy (Appendix 3) 

that have considered smoking in people with type 2 diabetes in relation to kidney function. 

Relevant details of these studies are summarized in Table 15. All of these studies showed an 

association between smoking and albuminuria. Only one cohort study was found which 

included an assessment of smoking as a risk factor for eGFR namely Gambaro et al (2001). 

Of the 7 prospective cohort studies identified only one small study (Smulders et al 1997a) 

reported no significant association between smoking and the progress of albuminuria. 

Chuahirun & Wesson (2002) prospectively sought predictors of renal function decline in 33 

people with type 2 diabetes, successfully targeting a mean blood pressure goal of 92 mm 

Hg (about 125/75 mm Hg) with antihypertensives including ACEi. Initial plasma creatinine 

was < 1.4 mg/dL, follow-up 64.0 +/- 1.1 months. Regression analysis showed that smoking 

was the only examined parameter that significantly predicted renal function decline. In the 13 

smokers, serum Cr increased from 1.05 +/- 0.08 mg/dL to 1.78 +/- 0.20 mg/dL although 

MAP was the same. The 20 non-smokers had a lesser Cr rise at 1.08 +/- 0.03 mg/dL to 

1.32 +/- 0.04 mg/dL. 

The 6 month prospective cohort studies of Chuahirun et al (2004) concluded that cigarette 

smoking exacerbates renal injury despite adequate blood pressure control with ACEi. 

Smoking cessation by those with microalbuminuria was associated with amelioration of the 

progressive renal injury caused by continual smoking. The smaller but long term study by 

Chuahirun et al (2003) concluded that smoking and increased UAE are interrelated predictors 

of nephropathy progression and that smoking increases UAE in patients despite improved 

BP control and ACE inhibition. 

The prospective cohort study reported by Cederholm et al (2005), included 6513 people with 

type 2 diabetes with 5 year follow up period. Smoking was identified as an independent risk 

factor for established microalbuminuria and for the development of microalbuminuria. 

Similarly the retrospective cohort study reported by Gambaro et al (2001), used logistic to 

show that smoking was the most important risk factor for progression of nephropathy. The 


authors concluded that quitting smoking should be part of the prevention therapy. The OR 

for smoking and development of microalbuminuria in a prospective cohort study of 930 

people with type 2 diabetes and high cholesterol reported by Biarnes et al (2005) was 3.19 

(95% CI 1.02-9.96). 

The large cohort study of people with type 2 diabetes receiving dialysis treatment by 

Braatvedt et al (2006), concluded that dialysis patients with a history of smoking had the 

highest all cause mortality. 

In addition to the prospective cohort studies, a number of cross sectional studies were 

identified by the search strategy (Appendix 3). These provide a lower level of evidence for 

the assessment of smoking as a risk factor for CKD. A total of 11 cross sectional studies 

have been identified the details of which are summarised in Table 15. All of the studies 

identified smoking to be associated with or to be a predictor of albuminuria. 


Table 15: Summary Tables of Studies of Smoking as Risk Factor for the Development and Progression of CKD in People with Type 2 

Diabetes 

Study ID Study Design Outcome 


Anan et al (2007) Cross sectional. 

Type 2 diabetes premenopausal 

women, 

n=20/35 

(Smokers/non smokers) 

Baggio et al (2002) 

Biarnes et al (2005) 

Bruno et al (1996) 

Cederholm et al (2005) 

Chuahirun et al (2003) 


Corradi et al (1993) 

Cross sectional 

Type 2 diabetes with abnormal AER 

n=96 


Type 2 diabetes, high cholesterol 

n=930 



n=1574 



4097 (Type 1 diabetes) 

6513 (Type 2 diabetes) 


Type 2 diabetes undergoing BP control 

n=84 


Type 2 diabetes with and without 

macroalbuminuria. Smoking cessation 

in Type 2 diabetes microalbuminuria 

n= 237 


Type 2 diabetes, hypertensive, males 

n=90 

Follow up Comments/Conclusions 

(mths) 

UAE UAE was independently associated with current smoking 

suggesting smoking as a risk factor for development of 

increased UAE 

UAE, GFR, GBM width Smoking affects glomerular structure and function in Type 2 

diabetes and may be an important factor for the onset and 

progression of diabetic nephropathy. 

Albuminuria 24 OR for smoker and development of microalbuminuria 3.19 

(1.02-9.96) 

UAE Smoking habits are independently related to both micro and 

macroalbuminuria 

Albuminuria 60 Smoking identified as an independent risk factor for 

established microalbuminuria and for the development of 


Plasma creatinine, UAE 64 Smoking and increased UAE are interrelated predictors of 

nephropathy progression and smoking increases UAE in 

patients despite improved BP control and ACE inhibition. 

Urine excretion of 

TGFbetaV, UAE 

6 Cigarette smoking exacerbates renal injury despite BP control 

and ACEi – cessation by those with microalbuminuria 

ameliorates the progressive renal injury caused by continual 

smoking. 

UAE The determinants of a decrease in UAE after lisinopril 

treatment were the duration of hypertension in non smokers 

and daily tobacco consumption and duration of smoking in 

smokers. Smoking may be an independent determinant of 

microalbuminuria in hypertensive individuals. 




Dean et al (1994) 


Type 2 diabetes, normotensive 

n=87 

Forsblom et al (1998) 

Gambaro et al (2001) 

Gatling et al (1988) 

Ikeda et al (1997) 

Nilsson et al (2004) 

Pijls et al (2001) 

Savage et al (1995) 

Smulders et al (1997a) 

Retrospective cohort 


n-134 

Retrospective cohort 

Italy 


n=273 



n=842 


Type 2 diabetes – men 

n=148 



Hospitals, primary health care 

n= >17000 type 2 diabetes 


Type 2 diabetes – primary care patients 

n=335 


Type 2 diabetes with appropriate BP 

control 

n=933 


Type 2 diabetes with microalbuminuria 

n=58 


(mths) 

UAE Relationship if any between smoking and UAE not stated in 

abstract. 

UAE 108 There was an over-representation of smokers (55% vs. 27%; 

p=0.01) in people who progressed to micro- or 

macroalbuminuria vs. those who did not progress. 

AER, serum creatinine. 36 Logistic regression – smoking was the most important risk 

factor for progression of nephropathy. Quitting smoking 

should be part of the prevention therapy. 

UAE, ACR Significant association found between UAE and smoking 

category. 

ACR OR for the prevalence of micro/macroalbuminuria was 

significantly higher for smokers than ex smokers. 

Albuminuria Smoking was associated with poor glycaemic control and 


ACR Smoking independently associated with ACR. 

UAE The most significant predictors of micro and macroalbuminuria 

were systolic hypertension, BMI, HDL, insulin use and 

smoking pack years. 

ACR 24 Smoking was not a significant predictor of the progress of 

albuminuria 




(relevant to CKD) (mths) 

Thomas et al (2006) Cross section 

Type 2 diabetes Chinese males 

n=496 

ACR ACR elevated in smokers. Smoking was associated with a 

more adverse metabolic profile and peripheral vascular disease. 

Male smokers compared to never smokers had lower HDLcholesterol 

levels (1.12 +/- 0.31 vs. 1.20 +/- 0.30 mmol/L, p = 

0.006), and elevated albumin-to-creatinine ratio (3.57 (2.68- 

4.75) vs. 2.47 (1.99-3.05) mg/mmol, p = 0.040). 


Summary – Prevention and Management of Chronic Kidney 

Disease in Type 2 diabetes? 

• Given the strong association between type 2 diabetes and ESKD, strategies aimed at 

prevention of type 2 diabetes are also relevant to the prevention of CKD. 

• Effective control of blood glucose has been shown to reduce the progression of CKD in 

people with type 2 diabetes. There is some evidence to suggest that HbA1c targets below 

that recommended for the management of type 2 diabetes may have beneficial outcomes 

with respect to CKD. However, the same evidence suggests that lower targets may have 

adverse outcomes or at best no effect on cardiovascular events, which are a key focus in 

the management of type 2 diabetes. Furthermore, lower blood glucose targets are also 

associated with an increase in serious hypoglycaemic events. 

• Elevated blood pressure is strongly associated with the development of albuminuria in 

people with type 2 diabetes. Management of elevated blood pressure has been shown to 

influence the rate of progression of CKD as well as CVD and is thus a major focus of 

both prevention and management. 

• There is evidence to indicate that antihypertensive agents that act on the renin-angiotensin 

system (i.e. ACEi and ARB) have a renoprotective effect over and above that resulting 

from the effect on blood pressure. As a consequence use of these agents is favored in the 

treatment of elevated blood pressure in type 2 diabetes and has also lead to their use in 

normotensive people with type 2 diabetes. 

• Abnormal blood lipid profiles are strongly associated with the progression and severity of 

CKD in people with type 2 diabetes. Given the strong association between dyslipidaemia 

and CVD, management of blood lipid in type 2 diabetes is recommended irrespective of 

the presence of indicators of CKD. There is no evidence to suggest alternate management 

strategies are required for management of CKD. Nor is there evidence to show that lipid 

lowering prevents development or rate of progression of CKD in individuals with type 2 

diabetes. 

• There is limited evidence demonstrating a long term effect of dietary interventions on the 

progress of CKD in type 2 diabetes. There is some evidence to suggest that protein 

restriction may affect the rate of progress of CKD, however the clinical application of 

these interventions are questionable. Diet and lifestyle are, however important for the 

management of type 2 diabetes and CVD risk and thus likely to form a component of the 

overall management of an individuals risk profile irrespective of CKD. 

• In observational studies, smoking has been identified as a independent risk factor in the 

progression of CKD, and given the role of smoking as a strong risk factor in a range of 

other outcomes, including CVD, an individuals smoking cessation is an important 

recommendation irrespective of CKD. 



Prevention and Management of CKD 

i) Role of blood glucose control 

Author (year) 

Level 


Study Type 

Evidence (Intervention) 

Quality 

Rating 

Magnitude of 

the effect 

Rating 

Relevance 

Rating 

ADVANCE (2008) II RCT High High High 

Amador-Licona et al (2000) II RCT Medium Medium Low 

Bakris et al (2003) 

Rosigltazone 

II RCT Medium Medium Medium 

Davidson et al (2007) 

II RCT High High Medium 

De Jager et al (2005) 

HOME 

II RCT High Medium Medium 

Gaede et al (2003b) 

Steno2 

Multifactorial – includes use 

II RCT High High High 

of antidiabetics 

Gambaro et al (2002) II RCT High High Low 

Hanefeld et al (2004) 

II RCT High Medium High 

Johnston et al (1998a) 

Johnston et al (1998b) 

Lebovitz et al (2001). 

Levin et al (2000) 

Matthews et al (2005) 

Newman et al (2005) 

Ohkubo et al (1995) 

Richter et al (2006) 

Cochrane (Pioglitazone) 

Richter et al (2007) 

Cochrane (Rosiglitazone) 

Saenz et al (2005) 

Cochrane (Metformin) 

Schernthaner et al (2004) 

Pioglitazone vs. Metformin 

Shichiri et al (2000) 

Kunamoto Study 

UKPDS (1998c) 

II RCT Medium Low Medium 


II RCT High High Medium 

II 

RCT 

Medium (no 

blinding) 

Medium 

High 


I 

II 

I 

I 

I 

Systematic 

review of RCT 

RCT 

Systematic 

review of RCT 

Systematic 

review of RCT 

Systematic 

review of RCT 

High 

Medium (no 

blinding) 

Medium 

(Albuminuria) 

Low 

(GFR) 

High 

High 

High 

High Low Medium 




II RCT Medium High Medium 


(1) Magnitude of effect assessed in relation to overall outcome(s) relevant to CKD. A high effect maybe 

therefore be noted where there may be no significant difference between two agents, however both agents result 

in significant outcomes with respect to progression of CKD. 


ii) 

Role of blod Pressure Control 

a) Blood pressure as a risk factor 

Author (year) 


Level 

Study Type 

Evidence 

Quality Rating 

Magnitude of 

the effect 

Rating 

Relevance 

Rating 

ADVANCE (2007) 

and Galan et al ( 2008) II RCT High High High 

Kaiser et al (2003) 

Newman et al (2005) 

Ravid et al (1998b) 

Strippoli et al (2005) 

ACEs and ARBs. 


Antihypertensives 

UKPDS (1998d) 

Tight blood pressure 

control 

I 

I 

II 

I 

I 

Systematic 

review of 

RCTs 

Systematic 

Review of 

RCTs 

Prospective 

cohort 

Systematic 

Review of 

RCTs 

Systematic 

Review of 

RCTs 

High 

High 

Low 

High 

(albuminuria) 

Medium (GFR) 

Low (ESKD) 

High 

High 

High High High 

High 

High 

High 

(albuminuria) 

High 

(albuminuria) 

High. 

High. 



) Blood pressure control as an intervention 

Author (year) 


Level of Evidence Quality Magnitude of the Relevance 

Level Study Type Rating effect Rating (1) Rating 

ADVANCE (2007) and II RCT High High High 

Galan et al (2008) 

Agardh et al (1996) II RCT High High Medium 

Ahmad et al (1997) II RCT Medium High Medium 

Baba & -MIND Study II RCT Medium Low High 

Group (2001) MIND 

Bakris et al (2005) GEMINI II RCT Medium Medium High 

Barnett et al (2004) 


DETAIL 

Chan et al (2000) II RCT High High Medium 

Estacio et al (2006) II RCT Medium High (UAE) High 

Low (GFR) 

Fogari et al (2000) II RCT Medium High Medium 

Galle et al (2008) VIVALDI II RCT High High High 

Hamilton et al (2003) I Systematic High High High 

review of 

RCTs 

Hollenberg et al (2007) II RCT Medium Medium High 

Jennings et al (2007) I Systematic High Medium Medium 

review of 

RCTs 

Jerums et al (2004) II RCT High High Medium 

Kaiser et al (2003) I Systematic High Low High 

review of 

RCTs 

Lacourciere (1993) II RCT Medium High High 

Lacourciere et al (2000) II RCT High Medium Medium 

(Effect of ACEi and 

ARB) 

Low 

(Comparative effect 

of ACEi and ARB) 

Lebovitz et al (1994) II RCT High High Medium 

Marre et al (2004) 

II RCT High Low High 

DIABHYCAR 

Muirhead et al (1999) II RCT High High 

Medium 

(effects on AER) 

Low 

(comparative effect 

of ACEi and ARB) 

Nakamura et al (2002) II RCT Medium Medium Medium 

Newman et al (2005) I Systematic High High (albuminuria) High 

Review of 

RCTs 

Medium (GFR) 

Low (ESKD) 

ONTARGET (2008) and II RCT High Low Medium 

Mann et al (2008) 

Parving et al (2001) and II RCT High High High 

Brenner et al (2001) 

Parving et al (2008) II RCT High High Medium 


Blood pressure control as an intervention (cont.) 

Author (year) 


Level of Evidence Quality Magnitude of the Relevance 

Level Study Type Rating effect Rating (1) Rating 

Ravid et al (1993) II RCT High (first 

High 

Medium 

phase) 

Medium 

(second phase) 

Ravid et al (1998a) II RCT High High 

High 

(decline in kidney 

function and 

albuminuria) 

Low 

(overt nephropathy) 

Remuzzi et al (2006) 


Ruggenenti et al (1998) 

BENEDICT 

Rosei et al (2005) CENTRO II RCT Medium Low Low 

Sano et al (1994) II RCT Medium High Medium 

Schram et al (2005) II RCT Medium Low Medium 

ABCD Schrier et al (2002) II RCT Medium High High 

Estacio et al (2000) 

Estacio & Schrier (1998) 

SMART Group (2007) II RCT Medium Medium Medium 

Strippoli et al (2005)ACEs 

and ARBs. 

I Systematic 

Review of 

High High (albuminuria) High. 


Antihypertensives 

I 

RCTs 

Systematic 

Review of 

RCTs 

High High (albuminuria) High. 

Tan et al (2002) II RCT High High Medium 

The HOPE Study Group 

High 

(2000) 

II RCT High High 

(reduction in risk of 

overt nephropathy) 

Low 

(risk of new 

microalbuminuria) 

Trevisan & Tiengo (1995) II RCT High High Medium 

UKPDS (1998b) Efficacy of II RCT High High High 

ACEi vs. beta 

UKPDS (1998d) 


Tight blood pressure control 

Viberti (2002) MARVAL II RCT Medium High High 

Yasuda et al (2005) II RCT Medium High Medium 

(1) Magnitude of effect assessed in relation to overall outcome(s) relevant to CKD. A high effect maybe therefore be noted where there may 

be no significant difference between two agents, however both agents result in significant outcomes with respect to progression of CKD. 


iii) 

Role of blood lipid modification 

Author (year) 

Ansquer et al (2005) 

DAIS – sub group 

analysis 

Fenofibrate 

Athyros et al (2004) 

CREACE Study 

Endo et al (2006) 

Probucol 

Fried et al (2001) I Systematic 

review of 

RCTs 

Gaede et al (2003b) 

Steno2 

Multifactorial – 

includes use of 

hypolipidaemics 

Keating & Croom 

(2007) 

Fenofibrate 

Keech et al (2005) 

Radermecker & 

Scheen (2005) 

FIELD 

Fenofibrate 

Koren (2005) 

ALLIANCE 

Nagai et al (2000) 

Benzafibrate and 

pravastatin 

Nakamura et al (2001) 

Statin 

Sandhu et al (2006) 

Statins 




the effect 

Rating 

Rating 


II RCT Medium Medium Low 

II RCT High Medium Medium 

High 

Medium (eGFR) 

Low 

(proteinuria) 

II RCT High High (however 

not able to 

assign 

contribution 

from 

hypolipidaemics) 

I 

Systematic 

review of 

RCTs 

Low 

High 

High Medium High 


II RCT Medium Medium Low 


II RCT High Medium Low 

I 

Systematic 

review of 

RCTs 


Sorof et al (2006) II RCT High Low Medium 

Strippoli et al (2008) I Systematic High Low Medium 

Statins 

review of 

The Heart Protection 

Study (2003) 

Simvastatin 

RCTs 

II RCT High Medium (small 

difference in rate 

of decline in 

eGFR) 

Medium 

Magnitude of effect assessed in relation to overall outcome(s) relevant to CKD. A high effect maybe therefore be noted where there may be 

no significant difference between two agents, however both agents result in significant outcomes with respect to progression of CKD. 


iv) 

Role of diet modification 

Author (year) 




Quality Magnitude of 

Rating the effect 

Rating 

Relevance 

Rating 

ProteinRestriction 

Barsotti et al (1998) III-2 Non randomised Medium Medium Low 

trial 

de Mello et al (2006) III-1 Before and after High Medium Low 

pseudo 

randomised 

trial 

Dussol et al (2005) II RCT High Low Medium 

Gross et al (2002) II RCT Medium Medium Low 

Meloni et al (2004) II RCT, Medium Low Medium 

prospective 

Pijls et al (1999) II RCT Medium Medium Medium 

Pijls et al (2002) II RCT Medium Low High 

Pomerleau et al (1993) II RCT Medium Medium Low 

Robertson et al (2007) I Systematic High Medium Medium 

Reviews of 

RCTs and 

before and after 

trials 

Teixeira et al (2004) III-2 Before and after High Medium Low 

trial 

Wheeler et al (2002) III-2 RCT Medium Low Low 

Salt Restriction 

Houlihan et al (2000b) II RCT Medium Medium Low 

Houlihan et al (2002a) II RCT Medium Low (with Low 

respect to salt) 

Houlihan et al (2002b) II RCT Medium Medium Low 

Imanishi et al (2001) III-2 Before and after Medium Low Low 

Vedovato et al (2004) III-2 Before and Medium Medium Low 

after, pseudo 

randomisation 

Yoshioka et al (1998) III-2 Before and 

after, 

Randomization 

of order of diet 

Medium Low Low 

Dietary Fat 

Barnard et al (2006) II RCT Medium Medium Medium 

Cardenas et al (2004) III-2 Prospective Medium Medium Medium 

cohort 

Nicholson et al (1999) II RCT Medium Low Low 

Nielsen et al (1995) III-1 Pseudo Medium Low Low 

randomised trial 

Shimizu (1995) III-2 Comparative 

study – before 

and after trial. 



v) Role of smoking cessation 

Author (year) 

Anan et al (2007) 

Baggio et al (2002) 

Biarnes et al (2005) 

Braatvedt et al (2006) 

Bruno et al (1996) 

Cederholm et al (2005) 



Corradi et al (1993) 

Dean et al (1994) 

Forsbolm et al (1998) 

Gambaro et al (2001) 

Gatling et al (1988) 

Ikeda et al (1997) 

Nilsson et al (2004) 

Pijls et al (2001) 

Savage et al (1995) 

Smulders et al (1997a) 

Thomas et al (2006) 


Level 

IV 

IV 

II 

II 

IV 

II 

II 

II 

IV 

IV 

III-2 

III-2 

IV 

IV 

IV 

IV 

IV 

II 

IV 

Study Type 

Cross 

sectional 

Cross 

sectional 

Prospective 

cohort 

Prospective 

cohort 

Cross 

sectional 

Prospective 

cohort 

Prospective 

cohort 

Prospective 

cohort 

Cross 

sectional 

Cross 

sectional 

Retrospective 

cohort 

Retrospective 

cohort 

Cross 

sectional 

Cross 

sectional 

Cross 

sectional 

Cross 

sectional 

Cross 

sectional 

Prospective 

cohort 

Cross 

sectional 

Evidence (Prognosis) 

Quality Rating 

Magnitude of 

the effect 

Rating 

Relevance 

Rating 


Medium High Medium 


High High Medium 

















Section 3: Cost Effectiveness and Socioeconomic 

Implication 

Question 

Is the prevention and management of chronic kidney disease in people with type 2 diabetes 

cost effective and what are the socioeconomic implications? 


• Based on favourable cost studies, screening for microalbuminuria and treatment with 

antihypertensive medications should be routinely performed for the prevention and 

management of kidney disease in people with type 2 diabetes. 

• Socio-economic factors should be considered when developing programs for prevention, 

and management of CKD in people with type 2 diabetes. 


• Screening people with type 2 diabetes for microalbuminuria and intensive treatment of 

those with elevated blood pressure with ACEi and ARB antihypertensive agents is 

supported by cost effectiveness studies. 

• Socio-economic status is an independent risk factor for CKD in people with type 2 

diabetes. 

Evidence Level III 

• Socio-economic status is associated with reduced access to primary medical care 

services and a lower level of utilisation of those services and this is likely to be 

associated with poorer outcomes in relation to CKD in people with type 2 diabetes. 

Evidence Level IV 


Background – Cost Effectiveness and Socioeconomic 

Implications of Prevention and Management of CKD in 

Type 2 Diabetes 

Cost Effectiveness 

Microalbuminuria is an asymptomatic condition that affects 20-40% of people with type 2 

diabetes. Of these, only about 20% are normotensive by current criteria. The rate of 

progression of microalbuminuria is slower in normotensive than in hypertensive people. Its 

significance arises from the proportion of affected people (40-80%) who subsequently 

develop either CVD or who develop proteinuria with eventual progression to renal failure 

(Palmer et al, 2008). ESKD causes a significant decline in quality of life, is expensive, and is 

associated with considerable mortality - approximately 15 per 100 patient years of 

Australians undergoing dialysis die annually (Australian and New Zealand Dialysis and 

Transplant Registry 2007). Based on a review of clinical trials Palmer et al (2008) estimated 

a risk multiplier of 3.29 for mortality in people with type 2 diabetes, elevated blood pressure 

and overt nephropathy compared to those with no nephropathy. In the Australian health 

sector, costs for provision of ESKD health care services has been projected to increase in the 

order of $A50M per year and reach more than $A800M by 2010 (Cass et al, 2006). This 

reflects the increasing prevalence of dialysis dependent patients and costs in the order of 

$A40,000 to $A45,000 per person per year (Craig et al, 2002). These ESKD cost projections 

exclude the costs associated with co-morbid conditions such as CVD as well as indirect or 

non-health sector costs associated with ESKD (Cass et al, 2006). 

Similarly, in the US, O'Brien et al (1998) highlighted that the direct costs arising from ESKD 

were the most expensive of 15 different complications of type 2 diabetes. ESKD in the US 

costs US$53,659 per annum per patient. In comparison, ischaemic stroke has an event cost of 

US$40,616 and annual cost of US$9,255 and a myocardial infarction has an event cost of 

US$27,630 and an annual cost of US$2,185. 

The cost-effectiveness of different prophylactic strategies in type 2 diabetes has not been 

compared. It has been estimated that the natural history of type 2 diabetes will see 17% of 

people developing end stage renal failure compared to 39% who will develop cardiovascular 

complications (Eastman et al, 1997). The latter are the dominant considerations in the elderly 

microalbuminuric person with type 2 diabetes and the HOPE study suggested that ACE 

inhibition would be justified for macrovascular protection alone in this subgroup (The HOPE 

Study Group 2000). 

Treatment with ACEi and ARBs reduces the chance of progressing from microalbuminuria to 

overt proteinuria and the chance of progressing from overt proteinuria to ESKD (Strippoli et 

al, 2005; Strippoli et al, 2006) . However, the long-term effects (over 10 years of therapy) of 

ARB or ACEi on kidney function in type 2 diabetes are less clear. In addition, assessment of 

the effects of ARB or ACEi in normotensive, microalbuminuric people with type 2 diabetes 

need to take into account the potential cardiovascular benefits. 

The review by Boersma et al (2006) focused on the pharmacoeconomics of ARB and ACEi 

treatment of people with type 2 diabetes and nephropathy. The conclusion with respect to 

ARBs was considered unequivocal in that the trials show both health gains and net cost 

savings compared to conventional treatment therapy, largely because of the high cost of 

dialysis and transplantation. The outcome with respect to the use of ACEi was concluded to 

be less clear due to the limited head-to-head trials comparing ACEi to ARB. 


It has been demonstrated that aggressive blood pressure reduction in hypertensive, 

normoalbuminuric people with type 2 diabetes reduces the incidence of microalbuminuria 

(UKPDS 1998b). Taken together with the progressive lowering of recommended blood 

pressure thresholds for initiating treatment of elevated blood pressure (Fulcher et al, 2004), it 

is possible that transition rates between stages of diabetic kidney disease will be 

substantially lower in the future than suggested by previous studies (Ravid et al, 1993; Ravid 

et al, 1998). 

It is important to note the assumptions inherent in cost-effectiveness analyses. A major 

concern about cost-effectiveness analysis is the validity of extrapolating to different 

populations in which costs, risk of diabetic kidney disease and effects of treatment on 

progression to renal failure may differ from the study population. 

Socio-economic Implications 

Socio-economic differentials in health are widely recognized with individuals of lower 

socioeconomic status (SES) having a higher risk for mortality and morbidity compared with 

those of higher SES e.g. (Adler & Ostrove 1999; Bello et al, 2008). These guidelines 

consider evidence for socioeconomic influences as they relate to outcomes relevant to the 

prevention and management of CKD in people with type 2 diabetes. 

The increasing prevalence of type 2 diabetes has been identified as the prime cause for the 

increasing prevalence of ESKD in Australia (Australian and New Zealand Dialysis and 

Transplant Registry 2007; Dunstan et al, 2002). The duration of diabetes, age, blood pressure 

control and blood glucose control have been identified in the Australian population as 

independent risk factors for the development of albuminuria (Tapp et al, 2004). Thus the 

consideration of the impact of socioeconomic factors on the diagnosis, prevention and 

management of CKD in people with type 2 diabetes, needs to be cognisant of factors that 

influence the development and treatment of type 2 diabetes, or that influence the likelihood of 

having undiagnosed diabetes and poorly treated hypertension and blood glucose. It is 

reasonable to assume that socioeconomic factors that influence the diagnosis and 

management of type 2 diabetes will also be important factors relevant to the progression of 

CKD. As the evidence relating to socioeconomic influences on the, prevention, detection 

and diagnosis of type 2 diabetes is addressed in other type 2 diabetes guidelines, this 

guideline focuses on factors that relate specifically to CKD following diagnosis of type 2 

diabetes. 

Socio-economic status may influence the diagnosis, prevention and management of CKD in 

people with type 2 diabetes as a consequence of the following (Cass et al, 2004): 

• Differing access to medical services. 

• A differing standard of service once accessed. 

• Late referral to treatment and/or specialist care. 

• Differing compliance with interventions. 

• Differing outcomes of interventions. 

• Difference in the prevalence of risk factors (e.g. smoking). 

As discussed in the overview to these guidelines, people from disadvantaged and transitional 

populations are disproportionally affected by type 2 diabetes and CKD. Factors contributing 

to the high incidence rates of ESKD in these groups include a complex interplay between 

genetic susceptibility, age of onset of diabetes, glycaemic control, elevated blood pressure, 

obesity, smoking, socioeconomic factors and access to health care. Within the Australian 


population, Indigenous Australians have an excess burden of both type 2 diabetes, 

albuminuria and ESKD e.g. (Australian and New Zealand Dialysis and Transplant Registry 

2007; Guest et al, 1993; Hoy et al, 2007; McGill et al, 1996; Preston-Thomas et al, 2007; 

Spencer et al, 1998) and likely represent the most marginalised group within the Australian 

health care setting. 

Explanations offered for the excess burden of kidney disease in Indigenous populations can 

be categorised as (Cass et al, 2004): 

• Primary renal disease explanations, for example greater severity and incidence of 

diseases causing ESKD. 

• Genetic explanations. 

• Early development explanations. 

• Socio-economic disadvantage. 

During 1991 – 2001, 47% of ESKD cases were attributed to diabetic nephropathy among 

Indigenous Australians, compared to 17% in non-Indigenous Australians. However, low 

kidney biopsy rates for ESKD, approximately 20% for both non-Indigenous and Indigenous 

Australians, indicate a potential for reporting bias with respect to diabetic nephropathy. 

Indigenous Australians have a higher rate of comorbidity than non-Indigenous Australians 

reflecting the generally poorer health of this group. It should be noted, however that type 2 

diabetes constitutes the greatest excess comorbidity among Indigenous ESKD entrants 

(McDonald & Russ 2003a; McDonald & Russ 2003b). Socio-economic factors that influence 

the health of Indigenous Australians and other marginalised groups within the Australian 

population are likely to affect detection, prevention and management of CKD in people with 

type 2 diabetes. The high prevalence of type 2 diabetes causing ESKD amongst Indigenous 

Australians, and the association between poor control of diabetes and risk of progression of 

CKD, are consistent with disadvantage being a significant determinant of progression of 

kidney disease in diabetes. 

Cass et al (2002) note that the evidence for the association between socioeconomic status and 

the incidence of ESKD is inconsistent. A study of the association between the level of 

socioeconomic disadvantage for a capital city area and the incidence of ESKD showed higher 

ESKD rates in more disadvantaged areas (Cass 2002). A similar study of indicators of 

socioeconomic disadvantage amongst Indigenous Australians (at a regional level) and the 

incidence of ESKD has shown a strong correlation with an overall rank of socioeconomic 

disadvantage. Indigenous ESKD patients are more likely to be referred to a nephrologist late 

in the course of their renal disease. Late referral is associated with increased mortality on 

ESKD treatment and is more common in disadvantaged areas. Amongst Indigenous ESKD 

patients, a poor understanding of their own CKD has been linked to non-compliance and 

reduced active involvement in their own management (Anderson et al 2008). Reduced 

engagement with care providers and services is a risk factor for poor outcomes with CKD 

care. 


Evidence - Cost Effectiveness and Socioeconomic 

Implications of Prevention and Management of CKD in 



• Screening people with type 2 diabetes for microalbuminuria and intensive 

treatment of those with elevated blood pressure with ACEi and ARB 

antihypertensive agents is supported by cost effectiveness studies. 

The cost effectiveness of intensive blood pressure control in people with type 2 diabetes, 

elevated blood pressure and normoalbuminuria, has been evaluated in the UKPDS over a 

mean interval of 8.8 years (UKPDS 1998a). The intensive blood pressure control group 

(n=758) achieved a mean arterial pressure of 103 mmHg (144/82 mmHg) compared with 109 

mmHg (154/87mmHg) in the usual treatment group (n=390). Use of resources driven by trial 

protocol and in standard clinical practice were compared. The main outcome measures were, 

firstly, cost effectiveness ratios calculated from use of healthcare resources and, secondly, 

within-trial time free from diabetes-related endpoints and projected estimates of life years 

gained. Compared with use of resources in standard clinical practice intensive blood pressure 

control was associated with an incidental cost of £1049 per extra year free from end points 

(costs and effects discounted at 6% per year). When the analysis was extended to life 

expectancy, the incremental cost per life year gained was £720, using the same discounting 

procedures. This analysis represents the first evidence suggesting that tight control of blood 

pressure for hypertensive people with type 2 diabetes offers a cost effective means of 

reducing the risk of complication and improving health (UKPDS 1998a). 

In a further analysis of the UKPDS study, an evaluation of the cost effectiveness of intensive 

blood pressure control with atenolol (n=358) vs. captopril (n=758) was performed (Gray, 

2001). There was no significant difference in life expectancy between groups. However, the 

cost per person in the captopril group was £935 greater than in the atenolol group, because of 

the lower drug price and fewer admissions to hospital in the atenolol group despite having 

higher antidiabetic drug costs. The analysis suggests that in hypertensive people with type 2 

diabetes and with normal AER, control of blood pressure based on beta blockers appears 

superior from a cost perspective to control based on ACEi (Gray 2001). It is important to note 

that this does not apply to people with increased AER, in whom treatment with renin 

angiotensin system inhibitors has been shown to reduce AER to a greater clinical extent than 

treatment with other agents (Kasiske et al, 1993; Weidmann et al, 1995). 

The Kidney Health Australia (KHA) report “The Cost–Effectiveness of Early Detection and 

Intervention to Prevent the Progression of Chronic Kidney Disease in Australia.” (Howard et 

al, 2006) undertook cost effectiveness modelling of “opportunistic screening and bestpractice 

management of diabetes, elevated blood pressure and proteinuria among Australian 

adults”. The model outcomes were used as input to the companion KHA report by Cass et al 

(2006) The study modelled the health outcomes of Life Years Saved and Quality Adjusted 

Life Years Saved. On the basis of the models the authors concluded that the best available 

evidence supports screening and intensive management of three risk factors for CKD, namely 

diabetes, high blood pressure and protein in urine (Cass et al, 2006). 


The KHA report included modelling the cost-effectiveness of screening for proteinuria and 

subsequent treatment with an ACEi for people with diabetes with or without elevated blood 

pressure. The authors noted that there was very limited data on both screening and treatment 

in normotensive patients, and thus model results are indicative only and suggested “some 

benefit under optimistic assumptions” with results considered as being of an exploratory 

nature only. Further trials were required in order to determine the cost effectiveness of ACEi 

interventions in microalbuminuric normotensive type 2 diabetes to be determined (Howard et 

al, 2006). 

More recently Palmer et al (2008) completed a health economic analysis of screening 

(microalbuminuria and overt nephropathy) and optimal treatment of nephropathy in 

hypertensive type 2 diabetes within the US health care system. The inputs to the economic 

modelling was based on estimates derived from a review of clinical trials. The modelling 

indicated screening for early stage nephropathy and optimal treatment (use of 300 mg 

irbesartan) in addition to the patients current treatment, results in a 44% reduction in the 

cumulative incidence of ESKD. The incremental costs-effectiveness ratio was in the order of 

$US20,000 per QALY gained for screening and optimised treatment compared to no 

screening. A 77% probability that screening and optimised therapy would be considered cost 

effective was calculated assuming a willingness to pay threshold of $US50,000. Overall the 

authors considered that the modelling showed that screening and optimised treatment (with 

an ARB) to “represent excellent value in a US setting.” 

In relation to screening and treatment with an ACEi for the early detection and treatment of 

kidney disease, Craig et al (2002) considered that whilst this was a promising primary 

prevention strategy for the prevention of ESKD, there was inadequate trial data to support 

population wide adoption (i.e. all middle and older aged Australians). This review was not 

limited to people with type 2 diabetes. Based on review of clinical trials and estimates of the 

performance characteristics of tests for proteinuria, it was estimated that screening of 20,000 

Australians (>50 years) would lead to subsequent treatment of 100 prescribed with ACEi and 

prevention of 1.3 cases of ESRF over 2 to 3 years. A cost benefit evaluation indicated a net 

cost saving to for the health care system assuming a one-off dipstick screening program in 

men and women over 55 based on assumed prevention of 205 cases of ESKD, 100% 

compliance with screening and best estimates of unit costs for screening and treatment. 

However, the cost effectiveness was quite sensitive to screening costs with a reversal point 

noted occurring at $2 per person compared to a base assumption of $0.50. Overall savings on 

the base assumptions were estimated at $A70,000 (2-3 years treatment costs for ESKD). 

Given the sensitivity of the estimates to key areas of uncertainty with respect to ESKD risk 

factors in the general population including, performance of screening tests and the benefits of 

ACEi treatment in screen-detected low risk-subjects, it remains unclear whether population 

wide screening for kidney disease would do “more harm than good.” Presumably these 

uncertainties would be lower in the higher risk type 2 diabetes sub group favouring adoption 

of screening and treatment in this setting. 

Given that microalbuminuria does not directly cause morbidity or mortality, the effectiveness 

of treating microalbuminuria can be assessed by comparing the cost of treatment to the 

savings resulting from the presumed prevention of end-stage kidney disease (Cass et al, 2006; 

Craig et al, 2002; Palmer et al, 2008). However, it should be emphasised that no study has 

followed the effects of ACEi or other intervention in normotensive, microalbuminuric people 

with type 2 diabetes until the development of ESKD. Nevertheless, such analysis can aid in 

determining which of several approaches provides the most cost-effective treatment of 

microalbuminuria. It should be noted that treatment of microalbuminuria is only one of 


several prophylactic programs that may benefit people with diabetes, and cost-benefit 

analyses provide a useful tool in the efficient allocation of limited health resources. 

The alternatives to screening for and treating diabetic microalbuminuria with ACEi or ARBs 

are to wait until elevated blood pressure (BP>130/85) or gross proteinuria develops before 

instigating therapy, or to treat all people with type 2 diabetes with ACEi or ARBs regardless 

of their urinary protein excretion. The costs and benefits for screening for albuminuria and 

subsequent treatment with an ARB, was considered by Palmer et al (2008) and discussed 

above. The costs and benefits associated with treatment of all people with type 2 diabetes 

with an ACEi have been modelled over the lifetime of a theoretical cohort of American 

people with diabetes aged 50 years at time of diagnosis and who were not receiving ACEi 

for other reasons by Golan et al (1999). In this model, the effectiveness of ACEi in slowing 

the progression of normoalbuminuria to microalbuminuria was based on only one randomised 

trial of 156 normotensive, middle-aged Israeli people (Ravid et al, 1998). This trial showed 

that ACEi therapy was associated with an absolute risk reduction of 12.5% (CI 2-23%) over 6 

years. The effectiveness of ACEi is slowing the progression of microalbuminuria to diabetic 

kidney disease was also based on one study by (Ravid et al, 1993). In 94 normotensive 

middle-aged Israeli people with type 2 diabetes, AER increased over 5 years from 123 to 310 

mg/24 hrs in the placebo group, and from 143 to 150 mg/24 hrs in the enalapril treatment 

group, showing a significant reduction in the rate of change of AER (p

Cost-effectiveness studies of screening and early treatment of diabetic kidney disease were 

initially performed in people with type 1 diabetes (Siegel et al, 1992). Two cost-effectiveness 

modelling procedures were performed, assuming conservative or optimistic effects of 50% 

and 75%, respectively, for ACE inhibition in slowing progression from microalbuminuria to 

overt kidney disease and from overt kidney disease to renal failure. The model showed that 

screening and treatment at the stage of microalbuminuria provided an additional 5 to 8 

months of life expectancy, when compared to late intervention at the stage of overt diabetic 

kidney disease . Screening and treatment at the microalbuminuric stage in type 1 diabetes 

yielded a cost of US$16,500 per life year saved in the conservative model, and US$7,900 per 

life year saved in the optimistic model (Siegel et al, 1992). 

Similar modelling procedures have been performed in people with type 2 diabetes. The costs 

of screening and treating microalbuminuria with ACEi include US$20/year for an annual 

check for microalbuminuria and US$320 for treatment with an ACEi. Whether this strategy 

increases physician/health carer time is unclear. The cost of screening for overt proteinuria is 

US$3 (Golan et al, 1999). 

It was estimated that screening and treatment with an ACEi at the microalbuminuric stage 

would cost US$22,900 per life year saved, when compared to waiting till overt diabetic 

kidney disease develops (Golan et al, 1999). This study also suggested that treating all 

middle-aged people with type 2 diabetes with an ACEi would cost US$7,500 per life year 

saved, when compared to delaying ACEi therapy till the microalbuminuric stage (Golan et al, 

1999). However, this 'treat all' approach has not been subjected to clinical trials and requires 

further cost-effectiveness evaluation. 

The life-time cost of ACEi treatment of microalbuminuria has been calculated as $14,940, 

compared to $19,520 if ACEi are only introduced after gross proteinuria develops (Golan et 

al, 1999). 

Data have been obtained on renal outcomes using angiotensin receptor blockade (Parving 

2001). Hypertensive people with type 2 diabetes and microalbuminuria were treated over 2 

years with irbesartan (150 mg/day or 300 mg/day) or placebo. The primary outcome was the 

time to the onset of diabetic kidney disease, defined by persistent albuminuria in overnight 

specimens, with a AER

Socio-economic Implications 

• Socio-economic status is an independent risk factor for CKD in people with 

type 2 diabetes (Evidence Level III). 

The prevalence and incidence of CKD is associated with socioeconomic status, whereby 

increasing social disadvantage is an independent risk factor for CKD in people with type 2 

diabetes. The following studies provide evidence relating to the influence of socioeconomic 

factors on CKD in people with type 2 diabetes. 

White and colleagues (White et al, 2008) sought to determine whether an elevated burden of 

CKD is found amongst disadvantaged groups living in the US, Australia and Thailand. The 

study used the NHANES III, AusDiab I and InterASIA databases and identified a prevalence 

of diabetes of 10.6% in the US, 7.4% in Australia and 9.8% in Thailand in people 35 years or 

older. Crude analysis showed income in the lowest quartile, shorter duration of education 

and being unemployed (p

(≥ 150µmol/L) with cases identified from a review of a database of chemical pathology 

results. The least and most deprived quintiles had rates of 1,067 per million population 

(pmp) per annum (95% CI 913 to 1,221) and 1,552 pmp per annum (95% CI 1,350 – 1,754). 

The nature of the study did not allow for adjustment for potential confounding factors such as 

BMI, smoking, hypertension etc. Furthermore the cause of CKD was not able to be estimated 

for the majority (87%) of the cases. 

A population based prospective study aimed at identifying how much of the excess risk for 

CKD among African Americans can be explained on the basis of racial disparities in 

potentially modifiable risk factors was conducted by Tarver-Carr et al (2002). The following 

explanations of the higher incidence of ESKD amongst African Americans were considered: 

• SES 

• Greater prevalence and severity of diabetes and hypertension 

• Increased inherited susceptibility to kidney damage. 

The study analysed baseline CKD risk factors from a non concurrent nationally representative 

population based cohort (NHANES II) with a 12 to 16 year follow up. Compared with white 

subjects, African American adults were more likely to have lower educational attainment, 

live below the federal poverty line and to be unmarried. They were also more likely to be 

current smokers, to be obese, to be physically inactive and to drink less alcohol. They had a 

higher prevalence of diabetes and hypertension as well as higher SBP and GFR. The ageadjusted 

incidences of all-cause CKD and treated ESKD were 2.7 and 8.9 fold higher 

amongst African Americans. The age-adjusted incidence of kidney disease attributable to 

diabetes was almost 12 times higher in African Americans. After adjustment for age and 

gender, sociodemographic factors, lifestyle factors and clinical factors, the excess risk of 

CKD among African Americans reduced from a relative risk of 2.69 (1.50-4.82) to 1.95 

(1.05-3.63); explaining 44% of the excess risk. Diabetes and hypertension alone accounted 

for 32% of the excess risk. The differences according to ethnicity were greater with middle 

aged than older adults. The authors concluded that interventions aimed at reducing racial 

disparity in CKD risk should focus on primary prevention and improved treatment of diabetes 

and hypertension, lifestyle modification, and elimination of health disparities attributable to 

socioeconomic status. 

The Fremantle Diabetes Study reported by Davis et al (2007), a longitudinal observational 

study in a community based clinically-defined type 2 diabetes patient cohort, compared the 

ACR in self-identified Aboriginal and Torres Strait Islanders (n=18) with Anglo Celt type 2 

diabetes patients (n=819), who represent the largest ethnic group within the patient 

community. The Aboriginal and Torres Strait Islander patients were significantly younger at 

diagnosis but had similar diabetes duration. Despite similar glycaemic management, the 

Indigenous patients had higher HbA1c. The geometric mean ACR was significantly higher in 

Aboriginal compared to Anglo Celt patients [10.1 (1.1-93.6) vs. 2.9 (0.7-12.4) mg/mmol 

respectively]. The SBP and DBP were lower and the smoking rate three times higher than in 

the Anglo Celt patients. Even though Aboriginal and Torres Strait Islander patients had a 

higher number of GP visits each year, they were less likely to have received diabetes 

education or to self monitor blood glucose. Overall there was no significant difference in the 

proportion of each group that died during the mean follow up period of 9.3 ± 3.2 years, 

however the age at death was 18 years younger in the Aboriginal group. Aboriginal patients 

had a twofold higher risk of dying than Anglo Celts. Amongst other variables, urinary ACR 

was an independent predictor of all-cause mortality in Aboriginal and Torres Strait Islander 

and Anglo Celt patients. The Fremantle Study, although the small number of Indigenous 

patients reduces the ability to draw inferences about the urban Indigenous population, 


suggests that sustained high-level glycaemia and smoking are likely determinants of 

albuminuria in the Indigenous patients. 

• Socio-economic status is associated with reduced access to primary medical 

care services and a lower level of utilisation of those services and this is likely 

to be associated with poorer outcomes in relation to CKD in people with type 

2 diabetes (Evidence Level IV). 

The mechanisms by which social disadvantage increases the risk of CKD have not been fully 

elucidated. However, social disadvantage appears to influence the stage of CKD at which 

specialist referral takes place, which in turn has negative implications for individual 

outcomes. Access to and utilisation of primary care medical services may also be lowest 

amongst those of highest social disadvantage and greatest need, thereby limiting the ability 

for implementation of interventions shown to prevent or reduce progression of CKD. 

Consideration of access to medical services needs to take into account both services related to 

prevention as well as specialist care for the management of CKD. Consistent with the study 

by Davis et al (2007), the socially disadvantaged are likely to be less educated in aspects of 

primary prevention and management. In relation to CKD, the timing of referral to a 

nephrologist might further influence the progression of CKD and overall outcomes. The 

meta analysis by Chan and colleagues (Chan et al, 2007) examined the outcomes in patients 

with CKD referred late to a nephrologists. The analysis did not distinguish between the cause 

of CKD nor conduct sub group analyses for diabetes. Overall, 20 studies (total sample size 

12 749) examining the effect of late referral met inclusion. The definition of late referral 

varied from 1 month to 6 months. There was a significantly increased overall mortality in the 

late referral group compared to the early referral group (relative risk 1.99 95% CI, 1.66 to 

2.39) and a significantly longer duration of hospital stay. However, the mean serum 

creatinine and creatinine clearance at time of referral were not significantly different between 

the groups. 

Cass et al (2003), investigated the association between area level measures of socioeconomic 

disadvantage and the proportion of ESKD patients who were referred late for renal 

replacement therapy. The analysis, which utilized the ANZDATA database, considered the 

timing of referral to a nephrologists and the postcode of residence at the start of treatment. 

Late referral was defined as those who required dialysis within 3 months of referral. The 

analysis was restricted to capital cities and excluded overseas visitors and those where ESKD 

was caused by disease with very short course. The ABS Statistical Sub-Division (SSD) level 

socioeconomic data from the 1996 census was used for the assessment. 

Of the total of 3334 patients (April 1995 – December 1998), 889 (26.7%) were found to have 

been referred late with a high variability between SSDs. There was a significant correlation 

between late referral and disadvantage (r=-0.36, p=0.01), with a higher proportion of late 

referral being associated with the more disadvantaged regions. Areas with higher incidence 

of ESKD in population terms were also areas where a higher proportion of patients were 

referred late. Issues of access, availability and quality of care are all potentially relevant to 

late referral. Disadvantaged areas had both an increased population burden of ESKD and a 

greater risk of delayed access to specialist renal services which is then associated with a 

poorer outcome. The study concludes that despite an overall improvement in the prevention 

and care of chronic diseases, with regard to chronic renal failure, there is a failure to address 

the needs of general practitioners and the public especially in disadvantaged areas. Of 

interest, late referral was found not to be related to geographical access to dialysis units (Cass 

et al 2003). 


Overland and colleagues analysed information on the number of diabetic individuals and 

number of services for selected Medicare item codes by NSW postcodes using the Health 

Insurance Commission data file (Overland et al, 2002). The analysis was conducted for the 

1996 calendar year and indicated that people at most disadvantage were less likely to be 

under the care of a GP (OR 0.41 0.40-0.41) or consultant physician (0.50 0.48-0.53) despite 

this group having the highest prevalence of diabetes. Once under care, slightly more were 

likely to undergo HbA1c or microalbuminuria screening (1.04 1.00-1.10 and 1.22 1.12-1.33) 

but less likely to undergo lipid or HDL cholesterol (0.81 0.48-0.53 and 0.85 0.79-0.90). Thus 

whilst disadvantaged people had poor access, once in the health system the level of 

monitoring received was similar. They note, however that the majority of medical 

practitioners are located in capital cities yet the majority of people in NSW at most social 

disadvantage live outside the Sydney metropolitan area. In addition the gap between 

Medicare reimbursement and the amount charged by medical practitioners is often greater in 

rural areas. People at most social disadvantage may be selectively disadvantaged in regard to 

access to health care services in the current system. The reluctance to test the most socially 

disadvantaged group for lipid abnormalities may reflect the cost of lipid lowering treatment 

(at the time of the survey). 

The relationship between social disadvantage and access to GPs is further demonstrated in 

the study by Turrell et al (2004) who conducted an analysis of 1996 to 1997 Medicare data to 

evaluate associations between utilization of GPs, socioeconomic disadvantage, geographic 

remoteness and Indigenous status. The review was undertaken at the level of Statistical 

Local Areas (SLA) after assigning an Index of Relative Socio-economic Disadvantage 

(IRSD) and Accessibility/Remoteness Index of Australia (ARIA). The proportion of 

Indigenous Australians was calculated from the number of self-identified persons of 

Aboriginal and Torres Strait Islanders background. In relation to socioeconomic 

disadvantage the following points were noted: 

• The number of full time equivalent GPs decreased with decreasing socioeconomic status 

and increasing remoteness of SLAs. 

• The proportion of Indigenous Australians increased with decreasing socioeconomic status 

and increasing remoteness of SLAs. 

• The utilization rate of GP services decreased markedly with the remoteness of the SLA 

and to a lesser extent with decreasing socioeconomic status. 

• There was an interaction between remoteness and socioeconomic disadvantage such that: 

- in highly accessible areas average GP utilization rate increased with decreasing SES 

- in remote/very remote areas, the average GP utilization rate decreased with decreasing 

SES. 

The authors concluded that in areas of adequate GP supply, ready geographic and financial 

access, equity of access appears to prevail. However, in socioeconomically disadvantaged 

areas where GPs are least accessible and affordable, the principle of equity of access to 

services is compromised. Furthermore, these latter areas are also those with highest medical 

needs. 


Summary – Cost Effectiveness and Socio-econmic 

Implications of Prevention of CKD 

• The best available evidence supports screening and intensive management of the three 

risk factors for CVD, namely diabetes, high blood pressure and protein in urine. 

• Screening for albuminuria in people with type 2 diabetes has been modelled as being cost 

effective due to the anticipated reduction in CVD events and the reduction in the number 

progressing to ESKD. The modelling shows cost effective outcomes both with respect to 

life years saved as well as quality adjusted life years saved. 

• Similarly treatment of albuminuria with ACEi and ARB antihypertensive agents is a cost 

effective approach to reducing CVD outcomes and progression to ESKD. 

• The cost effectiveness of treating normotensive microalbuminuric type 2 diabetes patents 

with an ACEi and/or ARB antihypertensive agent has yet to be established. 

• Further studies on the benefits of ACE inhibition in preventing ESKD in normotensive 

microalbuminuric people with type 2 diabetes would allow better estimates of the costeffectiveness 

of this treatment. However it may be difficult to ethically justify such 

studies 

• The prevalence and incidence of CKD is associated with socioeconomic status, whereby 

increasing social disadvantage is an independent risk factor for CKD in people with type 

2 diabetes. 

• The mechanisms by which social disadvantage increases the risk of CKD have not been 

fully elucidated. However, social disadvantage influences access and utilisation of 

medical services, thereby limiting the ability for implementation of interventions shown 

to prevent or reduce progression of CKD. 



Cost Effectiveness and Socioeconomic Implications 

Cost-effectiveness 

Author (year) 





Rating 

Cass et al (2006) N/A Modelling High High High 

Craig et al (2002) N/A Modelling High Medium High 

Golan et al (1999) N/A Modelling Medium High Medium 

Gray et al (2001) N/A Trial based High Medium Medium 

economic 

evaluation 

Howard et al (2006) N/A Modelling High Medium High 

Palmer et al (2008) N/A Modelling High High Medium 

Siegel et al (1992) N/A Modelling Medium High Medium 

UKPDS (1998a) N/A Trial based 

economic 

evaluation 



Socioeconomic implications 

Author (year) 





Rating 

Bello et al (2008) IV Crosssectional 


Cass et al (2003) III-3 Retrospective Medium High High 

cohort 

Chan et al (2007) I Systematic High High Medium 

review and 

meta analysis 

Davis et al (2007) II Prospective Medium High Medium 

cohort 

Drey et al (2003) III-3 Retrospective Low High Medium 

cohort 

Overland et al (2002) IV Crosssectional 


Tarver-Carr et al 

II Prospective Medium High Medium 

(2002) 

cohort 

Turrell et al (2004) IV Crosssectional 


Weng et al (2000) III-3 Retrospective Medium High Medium 

cohort 

White et al (2008) IV Crosssectional 

High Medium High 


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(2003). Development and progression of nephropathy in type 2 diabetes: the United Kingdom 

Prospective Diabetes Study (UKPDS 64). Kidney International. 63(1): 225-232. 

Adler, NE & Ostrove, JM (1999). Socioeconomic Status and Health: What We Know and 

What We Don't. Annals of the New York Academy of Sciences. 896: 3-15. 

Adler, SG, Pahl, M,Seldin, MF (2000). Deciphering diabetic nephropathy: progress using 

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APPENDICES 


Appendix 1: Search yield table 

Guideline Search Strategy and Yield 

Electronic databases searched: 

• Medline 

• EMBASE 

• Cochrane Library 

• CINAHL 

• HTA 

• DARE 

Terms used to search the databases: 

Detailed in search strategy and terms tables (Appendix 3). The tables include search terms used 

for Medline search and Cochrane. These search terms have been modified as appropriate for 

other databases. 

Search inclusion criteria: 

See general and specific inclusion and exclusion criteria (Appendix 3). Where possible searches 

were limited by the English language and human research. Literature searches were completed 

on the following dates: 

• Question 1: March 28, 2008. 

• Question 2: 

− Blood Glucose - April 3, 2008 

− Blood Pressure - March 18, 2008 

− Blood Lipids – March 27, 2008 

− Dietary Factors – March 28, 2008 

− Smoking Cessation – April 1, 2008. 

• Question 3: 

− Cost effectiveness - August 1, 2008 

− Socioeconomic implications - January 5, 2009. 

No additional formal searching of the electronic databases was performed after these dates. 

However, if important and relevant studies published after these dates were identified or brought 

to our attention before the completion of the guideline (March, 2009) they have been included. 

Abbreviations and explanation of table headings 

Identified = number of articles which matched the mesh terms listed or contained the text terms 

in each particular database 

Relevant = those articles considered relevant to the questions being asked after viewing titles or 

abstracts 


Articles identified by other strategies = including articles or reports suggested by the Expert 

Advisory Group or other experts or public submissions 

Total for Review = those articles considered relevant to the question after viewing titles and 

abstracts, contained original data or were systematic reviews of original articles and met the 

inclusion/exclusion criteria 

Total no. reviewed and graded = articles used to generate the evidence for the identified 

question . These articles have been summarised and graded 

Total no. reviewed and graded = articles used to generate the evidence for the identified 

question . These articles have been summarised and graded 


Questions 

1 How should kidney 

function be assessed 

and how often? 

2 How should CKD be 

prevented and/or 

managed in people 

with type 2 diabetes 

What is the role of 

blood glucose 

control? 


blood pressure 

control? 

No. articles 

identified 

(all databases 

combined) 

No. relevant 

articles 

Articles 

identified by 

other 

strategies 

Total for 

review 

Total no. 

reviewed and 

graded 

1688 954 6 960 58 12 35 11 II 

907 187 4 185 21 4 17 I 

1875 630 12 642 42 6 38 I 

Level 

I 

Level 

II 

Level 

III 

Level 

IV 

Highest 

level of 

evidence 


blood lipid 

modification? 


diet modification? 


smoking cessation? 

3. Is the prevention and 

management of CKD 

in people with type 2 

diabetes cost 

effective and what 

are the 

socioeconomic 

416 112 3 115 15 4 11 I 

1493 474 1 475 23 1 14 8 I 

861 140 1 476 18 6 1 11 II 

1424 (cost 

effectiveness) 

24 

(socioeconomic 

implications) 

114 (cost 


12 


implications) 

4 (cost 


18 


implications) 

118 (cost 


30 


implications) 

8 (cost 


10 


implications) 

implications? 

* Reports/publications that did not appear in the search but were suggested by members of the Expert Advisory Group and as a result of public submissions. 

** Level not assigned due to a number of the studies being models. 

NA** 

1 

NA 

2 

NA 

3 

NA 

4 I 


Appendix 2: Inclusion and exclusion criteria 

Generic criteria used to determine the suitability of articles for review 

Inclusion criteria 

The following are the criteria of articles to be included in the literature review: 

• Present original data or reviews of original data 

• Focus on kidney disease in type 2 diabetes or include a cohort with type 2 diabetes 

and renal outcomes 

• Address one or more of the specified research question 

• Applicable to diabetes care or prevention in Australia 

• Conducted in humans 

• Conducted in appropriate population for the question being addressed 

• Other specific inclusion criteria for each guideline 

Exclusion criteria 

• Studies of inappropriate patient population 

• Articles and reviews which present the author’s opinion rather than evidence 

• Small review articles where the material is covered more adequately by more 

recent/or more comprehensive reviews 

• In vitro and animal studies 

• Genetic studies that are not clinically applicable 

Specific criteria used to determine the suitability of articles for review (CKD guideline) 

• Interventions that focus on the assessment, prevention and management of kidney 

disease in people with type 2 diabetes. 

• Where two or more articles appear to report data from the same group of subjects, 

only the most complete article should be used to generate data for the analyses. 

• The sample size should be 50 or more. 

• Exclude studies of inappropriate populations (small studies in populations not 

relevant to the Australian population). 

• Post hoc analyses unless they provide significant additional information not already 

covered in the original study report. 

• For question 2 (prevention and management of CKD – role of dietary modification) 

studies of population size less than 50 have and short duration have been included due 

the small number of large trials. 


Appendix 3: Search strategies and terms 

General 

The symbol / after a word indicates that it is a MeSH term and any article found by this 

method has been allocated to this subject heading used in the database; .mp indicates that that 

word was searched as a keyword in the database; *indicates that the search was more directly 

focused. Other abbreviations used were: ACR refers to: albumin-to creatinine.mp OR ACR 

mp; Antihypertensives refers to: Antihypertensive agents/ OR Antihypertensive.mp OR 

Blood pressure lowering.mp; Decline in GFR refers to: decline in GFR.mp OR decline in 

glomerular filtration rate.mp; GFR refers to: GFR.mp OR glomerular filtration rate.mp; GFR 

= glomerular filtration rate; AER = albumin excretion rate. The symbol C indicates results 

from Cochrane database search. A list of specific intervention agents for blood pressure, 

blood glucose and blood lipids, used in the Cochrane search are listed at the end of the search 

strategy table. 

Question Searches Result 

1. How should kidney 

disease be assessed and 

how often? 

Total for Question 

(albuminuria/ OR proteinuria/) AND (gold standard 

OR sensitivity OR specificity) 

(albuminuria/ OR proteinuria/ OR kidney function 

tests/ OR glomerular filtration rate/ OR glomerular 

filtration rate.tw OR gfr.tw OR estimated 

glomerular filtration rate.tw OR proteinuria/ OR 

creatinine/) [1] 

(albumin excretion rate.tw OR aer.tw OR acr.tw OR 

dipstick$.tw OR serum creatinine.tw OR ratio$.tw 

OR assess$.tw OR “Sensitivity and Specificity”/ OR 

snesitivity.tw OR “review”/) [2] 

a.mp AND ([1] AND [2]) AND Diabetes Mellitus, 

Type 2 

(kidney function tests/ OR glomerular filtration rate/ 

OR glomerular filtration rate.tw OR gfr.tw OR 

estimated glomerular filtration rate.tw OR 

proteinuria/ OR creatinine/) AND Diabetes 

Mellitus, Type 2/ 





Mellitus, Type 2/ - LIMIT to “reviews (sensitivity)” 

60 (C) 

90407 

30000946 

1688 

954 (after 

1999) 

1708 

936 







Mellitus, Type 2/ - LIMIT to “etiology 

(sensitivity)” 

741 

2. How should kidney 

disease be prevented 

and/or managed? 

Role of blood pressure 

Diabetes Mellitus, Type 2/ AND (Proteinuria/ OR 

Albuminuria/) 


Albuminuria/) 

- LIMIT to “review (sensitivity)” 


Albuminuria/) 

- LIMIT to “etiology (sensitivity)” 

[Diabetes Mellitus, Type 2/ AND (Proteinuria/ OR 

Albuminuria/) 

- LIMIT to “review (sensitivity)”] 

OR [Diabetes Mellitus, Type 2/ AND (Proteinuria/ 

OR Albuminuria/) 

- LIMIT to “etiology (sensitivity)”] 


Albuminuria/ OR Glomerular Filtration Rate) 


Albuminuria/ OR Glomerular Filtration Rate) – 

LIMIT to “reviews (sensitivity) 


Albuminuria/ OR Glomerular Filtration Rate/) – 

LIMIT to “etiology (sensitivity) 


Albuminuria/ OR Glomerular filtration rate/ OR 

Kidney function tests) 

Total for Question 

Diabetes Mellitus, Type 2 AND (Angiotensinconverting 

enzyme inhibitors/ OR aldosterone 

antagonisits/ OR angiotensin II Type 1 receptor 

blockers/ OR calcium channel blockers/ OR 

hydroxymethylglutaryl-coa reductase inhibitors/) [1] 

2230 

1260 

1083 

1663 

915 (after 

1999) 

470 

250 

201 

302 (C) 

1875 

[1] AND (meta analysis OR clinical trial.mp,pt.) 574 



Diabetes Mellitus, Type 2/ AND antihypertensive 1817 

agents/ [2] 

[2] AND (meta analysis OR clinical trial.mp.pt.) 501 

Diabetes Mellitus, Type 2/ AND Antihypertensive 

agents/ [3] 

[3] AND (antihypert* OR 

angiotensin* near inhibit OR angiotensin* near 

block OR aldoster* NEAR antag* OR calcium near 

channel blocker* OR Hyrdoxymethylglutaryl* near 

inhibit* OR [antihypertensive list] # 

495 (C) 

129 (C) 

Role of blood glucose 

Diabetes Mellitus, Type 2/ AND ((hypoglycaemic 

agents/ OR HbA1* OR glycaem* OR glycem*) 

AND (Albuminuria/ OR Proteinuria/)) 

Diabetes Mellitus, Type 2/ AND (Hypoglycaemic 

agents/ OR HBA1* OR glycaem* OR glycem* OR 

gluc* near control* OR hypogly* next agent* OR 

[hypoglycaemic agent list]## [1] 

[1] AND (Proteinuria/ OR Albuminuria/ proteinu* 

OR albuminu*) 

457 

204 (C) 

6 (C) 

Role of blood lipids 

Diabetes Mellitus, Type 2/ AND (Anticholesteremic 

Agents/ OR Antilipemic Agents/ OR lipid.tw OR 

LDL.tw.) AND (albumin$.tw OR Albumnuria/ OR 

Proteinuria/) [2] 

416 

limit [2] to clinical trial, all. 100 

Role of Dietary 

Modification 

Salt Restriction 

Diabetes Mellitus, Type 2/ AND (Type NEXT 2 

AND diabetes) AND (Anticholesteremic Agents/ 

OR Antilipemic Agents/ OR antichol* OR antilip* 

OR lipid.tw OR LDL.tw. OR albuminuria.tw OR 

proteinuria.tw OR Albumnuria/ OR Proteinuria/ OR 

[agent list]###) 

Diabetes Mellitus, Type 2/ AND (Sodium dietary/ 

OR dietary salt OR dietary sodium OR ((salt* OR 

sodium*) AND (restict* OR intake* OR change*))) 

[1] 

12 (C) 

319 

limit [1] to clinical trial, all 85 



(Diabetes Mellitus, Type 2/ or type near 2) AND 

(Sodium dietary/ OR dietary salt OR dietary sodium 

OR ((salt* OR sodium*) AND (restict* OR intake* 

OR change*))) 

3 (C) 

Role of dietary protein 

Diabetes Mellitus, Type 2/ AND (Dietary Proteins/ 

OR protein* diet* OR protein OR diet) [1] 

600 


Diabetes Mellitus, Type 2/ AND (Dietary Proteins/ 9 (C) 

OR protein* diet* OR protein OR diet) 

Dietary fat 

Diabetes Mellitus, Type 2 AND (Diet, fat-restricted/ 

OR saturat* OR monounsatur* OR polyunsat*) [1] 

575 


[2] AND (Albuminuria/ OR Proteinuria) 3 

(Diabetes Mellitus, Type 2/ OR Type NEXT 2 

diabetes) AND ((Diet, fat-restricted/ OR saturat* 

OR monounsatur* OR polyunsat*) 

29 (C) 

Smoking Cessation 

3. Is the prevention and 

management of chronic 

kidney disease in people 

with type 2 diabetes 

cost effective and what 

are the socioeconomic 

implications? 

Diabetes Mellitus, Type 2/ AND (Smoking/ OR 

Smoking Cessation/) 


Smoking Cessation/) AND (Proteinuria/ OR 

Albuminuria) 


Smoking Cessation/ OR smoking OR smok* near/3 

cess*) 

861 

112 

28 (C) 


Socioeconomic 

Implications 

Diabetes Mellitus, Type 2/ AND (Economics/ OR 1424 

cost.tw OR cost effect*.tw) [1] 

(Kidney Diseases/ OR Proteinuria/ OR 

355 594 

Albuminuria) [2] 

[1] AND [2] [3] 134 

Limit [3] to English 114 



Diabetes Mellitus, Type 2/ AND (Kidney Diseases/ 5247 

OR Proteinuria/ OR Albuminuria) [1] 

(Socioeconomic factors/ OR Socioeconomic 

257 941 

factors.tw OR social disadvantage.tw) [2] 

[1] AND [2] 24 

Limit [3] to English 24 

Notes 

# Acebutolol or Adrenomedullin or Alprenolol or Amlodipine or Atenolol or Bendroflumethiazide or Bepridil or 

Betaxolol or Bethanidine or Bisoprolol or Bretyliu* or Bupranolol or Captopril or arteolol or Celiprolol or 

Chlorisondamine or Chlorothiazide or Chlorthalidone or Cilazapril or Clonidine or Cromakalim or 

Cyclopenthiazide or Debrisoquin or Diazoxide or Dihydralazine or Dihydroalprenolol or Diltiazem or 

Doxazosin or Enalapril or Enalaprilat or Epoprostenol or Felodipine or Fenoldopam or Fosinopril or Guanabenz 

or Guanethidine or Guanfacine or Hexamethonium or Hexamethoniu* or Hydralazine or Hydrochlorothiazide or 

Hydroflumethiazide or Indapamide or Indoramin or Isradipine or Kallidin or Ketanserin or Labetalol or 

Lisinopril or Losartan or Mecamylamine or Methyldopa or Metipranolol or Metolazone or Metoprolol or 

Mibefradil or Minoxidil or Muzolimine or Nadolol or Nicardipine or Nicorandil or Nimodipine or Nisoldipine 

or Nitrendipine or Nitroprusside or Oxprenolol or Pargyline or Pempidine or Penbutolol or Pentoliniu* or 

Perindopril or Phenoxybenzamine or Phentolamine or Pinacidil or Pindolol or Piperoxan or Polythiazide or 

Prazosin or Propranolol or Protoveratrines or Ramipril or Reserpine or Saralasin or Teprotide or Ticrynafen or 

Timolol or Todralazine or Tolazoline or Trichlormethiazide or Trimethaphan or Veratru* or Vincamine or 

Xipamide 

## Acarbose or acetohexamide or buformin or carbutamide or chlorpropamide or glipizide or gliclazide or 

glyburide or insulin or insulin next isophane or insulin next long-acting or metformin or phenformin or 

tolazamide or tolbutamide 

### Azacosterol or Chitosan or Cholestyramine or Clofibrate or Clofibric next Acid or Dextrothyroxine or 

Doxazosin or Hydroxymethylglutaryl* next Reductase next Inhibitors or Lovastatin or Meglutol or Pravastatin 

or Probucol or Simvastatin or trans* next *chlorobenzaminomethyl* next cyclohexane or Bezafibrate or 

Butoxamine or Clofenapate or Clofibrate or Clofibric or Colestipol or Gemfibrozil or Halofenate or Meglutol or 

Nafenopin or Niacin or Niceritrol or Procetofen or Pyridinolcarbamate or Simvastatin or Triparanol 


Appendix 4: NHMRC Evidence Statement Grading Forms 

Key question(s): How should kidney function be assessed and how often in people with type 2 diabetes? 

Evidence table ref: 

1. Evidence base (number of studies, level of evidence and risk of bias in the included studies) 

(A) Cohort studies (prognosis level II) demonstrate that microalbuminuria predicts overt 

nephropathy and accelerated decline in GFR. 

(B) Cross sectional studies (diagnosis level III) provide data on the accuracy of AER and ACR. 

(C) Cohort and cross sectional studies (diagnosis Level III) provide data on estimation of GFR. 

Note: the prognostic studies that are evidence for (A) use the tests described in (B) and (C). It is 

therefore impossible to separate the prognostic implications and the tests completely and therefore 

these issues have been graded as one recommendation. 

2. Consistency (if only one study was available, rank this component as ‘not applicable’) 

Lower level of consistency for eGFR studies. A All studies consistent 

B 

C 

D 

A 

B 

NA 

Several Level I or II studies with low risk of bias 

One or two Level II studies with low risk of bias or SR/multiple Level III studies with low risk of bias 

C Level III studies with low risk of bias or Level I or II studies with moderate risk of bias 

D Level IV studies or Level I to III studies with high risk of bias 

Most studies consistent and inconsistency can be explained 

Some inconsistency, reflecting genuine uncertainty around question 

Evidence is inconsistent 

Not applicable (one study only) 

3. Clinical impact (Indicate in the space below if the study results varied according to some unknown factor (not simply study quality or sample size) and thus the clinical impact of the intervention could not be determined) 

Persistent microalbuminuria confers an approximately 5 fold increase in 

risk of overt nephropathy over 10 years. In addition microalbuminuria 

is a risk factor for CVD and ESKD. 

4. Generalisability 

5. Applicability 

A 

B 

C 

D 

A 

B 

C 

D 

A 

B 

C 

D 

Very large 

Moderate 

Slight 

Restricted 

Evidence directly generalisable to target population 

Evidence directly generalisable to target population with some caveats 

Evidence not directly generalisable to the target population but could be sensibly applied 

Evidence not directly generalisable to target population and hard to judge whether it is sensible to apply 

Evidence directly applicable to Australian healthcare context 

Evidence applicable to Australian healthcare context with few caveats 

Evidence probably applicable to Australian healthcare context with some caveats 

Evidence not applicable to Australian healthcare context 


Other factors (Indicate here any other factors that you took into account when assessing the evidence base (for example, issues that might cause the group to downgrade or upgrade the recommendation) 

EVIDENCE STATEMENT MATRIX 

Please summarise the development group’s synthesis of the evidence relating to the key question, taking all the above factors into account. 

Component Rating Description 

1. Evidence base B 

2. Consistency B 

3. Clinical impact A 

4. Generalisability A 

5. Applicability A 

Indicate any dissenting opinions 

RECOMMENDATION 

What recommendation(s) does the guideline development group draw from this evidence? Use action statements where 

possible. 

GRADE OF RECOMMENDATION 

B 

Kidney status in people with type 2 diabetes should be assessed by: annual screening for albuminuria; AND annual estimation of glomerular 

filtration rate (eGFR) and continue annual screening for all albuminuria and eGFR in the event of negative screening test. 


IMPLEMENTATION OF RECOMMENDATION 

Please indicate yes or no to the following questions. Where the answer is yes please provide explanatory information about this. This information will be used to develop the implementation plan for 

the guidelines. 

Will this recommendation result in changes in usual care? 

YES 

Are there any resource implications associated with implementing this recommendation? 

Will the implementation of this recommendation require changes in the way care is currently organised? 

Are the guideline development group aware of any barriers to the implementation of this recommendation? 

NO 

YES 

NO 

YES 

NO 

YES 

NO 


NHMRC Evidence Statement Grading Form 

Key question(s): How should chronic kidney disease be prevented and/or managed in people with type 2 diabetes? 

Role of blood glucose control. 



Several Level 1 and Level II intervention studies demonstrate that 

glycaemic control reduces the development and progression of CKD in 

people with type 2 diabetes. 


Glycaemic control consistently shown to affect the progression of 

albuminuria in people with type 2 diabetes, however the evidence of the 

effect of glycaemic control on ESKD and rate of decline in GFR is 

either inconsistent or limited. 

A 

B 

C 

D 

A 

B 

C 

D 

NA 



Level III studies with low risk of bias or Level I or II studies with moderate risk of bias 

Level IV studies or Level I to III studies with high risk of bias 

All studies consistent 






Risk reductions in the order of 30% for progression to A Very large 

microalbuminuria with intensive glycaemic control are indicated by B Moderate 

trials. 

C Slight 



D 

A 

B 

C 

D 

A 

B 

C 

D 

Restricted 














6. Evidence base A 

7. Consistency B 

8. Clinical impact A 

9. Generalisability A 

10. Applicability A 





possible. 

A 

Blood glucose control should be optimised aiming for a generalised HbA1c target ≤ 7%. 






YES 




NO 

YES 

NO 

YES 

NO 

YES 

NO 




Role of blood pressure control. 



Several Level I and II (aetiology and intervention) studies evaluating 

the progression of CKD in people with type 2 diabetes in association 

with blood pressure control and use of antihypertensive agents in 

hypertensive and normotensive people. 


High level of consistency with respect to association between blood 

pressure and progression of albuminuria. 

Less consistency for some specific renal endpoints and interventions 

due to smaller number of trials. 

A 

B 

C 

D 

A 

B 

C 

D 

NA 











The trials indicate risk reduction in development of microalbuminuria in A Very large 

T2DM patients of approximately 30%. 

B Moderate 

The trials indicate risk of progression from microalbuminuria to C Slight 

macroalbuminuria to be reduced and regression from microalbuminuria D Restricted 

to normoalbuminuria to be increased in T2DM patients by 

approximately 40 to 50%. 


Studies either exclusively type 2 diabetes or mixed type 1 and type 2 

diabetes. 


A 

B 

C 

D 

A 

B 

C 

D 











Hypertension is a key risk factor for macrovascular complications, including stroke, myocardial infarction and heart failure in T2DM patients, which 

indicates a need to treat hypertension irrespective of the risk or presence of albuminuria. 




11. Evidence 

base 

A 

12. Consistency B Lower consistency for some renal endpoints and interventions. 

A 

13. Clinical 

14. 

impact 

Generalisabil A 

15. 

ity 

Applicability A 





possible. 

A 

In people with type 2 diabetes and microalbuminuria or macroalbuminuria, ARB or ACEi antihypertensives should be used to protect against 

progression of kidney disease. 

The blood pressure of people with type 2 diabetes should be maintained within the target range. ARB or ACEi should be considered as 

antihypertensive agents of first choice. Multi-drug therapy should be implemented as required to achieve target blood pressure. 






YES 




NO 

YES 

NO 

YES 

NO 

YES 

NO 




Role of smoking cessation. 



Several prospective cohort studies (aetiology level II) and retrospective 

cohort studies (aetiology level III) indicate smoking as an independent 

risk factor in the progression of CKD. 


Smoking is consistently identified as an independent risk factor for 

CKD. 

A 

B 

C 

D 

A 

B 

C 

D 

NA 










3. Clinical impact (Indicate in the space below if the study results varied according to some 

unknown factor (not simply study quality or sample size) and thus the clinical impact of the intervention could not be determined) 

Smoking has been identified as an independent risk factor for CKD in 

people with type 2 diabetes, however the magnitude of risk has not been 

defined. 



A 

B 

C 

D 

A 

B 

C 

D 

A 

B 

C 

D 

Very large 

Type 2 Diabetes Guideline 164 Chronic Kidney Disease, June 2009 

Moderate 

Slight 

Restricted 








Evidence not applicable to Australian healthcare context


Whilst the magnitude of the effect of smoking on CKD has not been defined, smoking influences a range of health endpoints relevant to the 

management of type 2 diabetes and other chronic disease. 




B 

16. Evidence 

base 

17. Consistency A 

18. Clinical 

impact 

19. Generalisabil 

20. 

ity 

Applicability A 


A-B Magnitude of effect of smoking on progression of CKD in type 2 diabetes patients has not been defined, however smoking 

has been identified as an independent risk factor. 

A 



What recommendation(s) does the guideline development group draw from this evidence? 

B 

Use action statements where possible. 

People with type 2 diabetes should be informed that smoking increases the risk of chronic kidney disease. 






YES 




NO 

YES 

NO 

YES 

NO 

YES 

NO 


Appendix 5: Overview of Guideline Development Process and 

Methods 


National Evidence Based Guidelines 

for the Prevention and Management of 


Overview of Guideline Development Process 


Methods 

Prepared by 


Menzies Centre for Health Policy 


for the 


Last updated 5 May 2009

Table of Contents 

Purpose and structure of the document……………………………………………………..1 

1.0 Introduction and Overview ........................................................................................ 3 

1.1 Diabetes as a health burden ........................................................................................... 3 

1.2 Key components and principles of diabetes care .......................................................... 4 

1.3 Rationale for the Guidelines .......................................................................................... 5 

1.4 Funding source .............................................................................................................. 6 

1.5 The Guideline Development Project Consortium ......................................................... 6 

1.6 The scope of the Guidelines .......................................................................................... 6 

1.7 Use of the Guidelines .................................................................................................... 6 

1.8 Review date ................................................................................................................... 7 

1.9 Economic analysis ........................................................................................................ 7 

1.10 Socio-economic impact ................................................................................................ 7 

2.0 Organisational structure and staffing ....................................................................... 8 

3.0 Methods ...................................................................................................................... 10 

3.1 Development of protocols. .......................................................................................... 10 

3.2 Guideline Development Process.................................................................................. 10 

4.0 Consultation Process ................................................................................................. 23 

References ............................................................................................................................. 27 

Appendices: ........................................................................................................................... 27 

Appendix i: Terms of Reference of the Steering Committee ….………………………30 

Appendix ii: Terms of Reference of the Expert Advisory Groups …………………… ..32 

Appendix iii: The NHMRC ‘interim’ level of evidence …………………… …………..33 

Appendix iv: Study Assessment Criteria …………………… ………………………….34 

Appendix v: NHMRC Evidence Statement Form …………………… ………………..34 

Appendix vi: Key stakeholder organisations notified of public consultation ……………40 

List of Tables: 

Table 1: Example of an Overall Assessment Report ............................................................. 15 

Table 2: Example of an evidence table with overall study assessment ................................. 15 

Table 3: NHMRC Body of Evidence Matrix ......................................................................... 18 

Table 4: Definition of NHMRC grades of recommendation ................................................. 19

Purpose and Structure of the Document 

Purpose 

This 2008-9 series of guidelines for type 2 diabetes updates and builds on the original suite of 

evidence based diabetes guidelines which were initiated in 1999 under funding from the 

Department of Health and Ageing (DoHA) to the Diabetes Australia (DA) Guideline 

Development Consortium. Under the initial diabetes guideline project, six evidence based 

guidelines for type 2 diabetes were endorsed by the NHMRC. The purpose of the initial 

guidelines and the current guidelines is to provide systematically derived, objective guidance 

to: 

1. Improve quality and consistency of care and reduce inappropriate variations in practice by 

assisting clinicians’ and consumers’ understanding of and decisions about treatment and 

management options 

2. Inform fund holders and health service planners about the effectiveness and feasibility of 

the various options 

3. Assist researchers and research authorities to highlight i) areas of diabetes prevention and 

care for which there is inconclusive evidence and ii) areas of deficiency in the evidence 

which require further or definitive research. 

The specific purpose of this current project which commenced in early 2008 was to update 

two of the previous guidelines - Primary Prevention, and Case Detection and Diagnosis – and 

to develop three new guidelines, one for Blood Glucose Control, one for Chronic Kidney 

Disease and one for Patient Education. 

Structure 

This Overview of the Guideline Development Process and Methods outlines the rationale for 

the guidelines and the organisational structure, methods and processes adopted for the Type 2 

Diabetes Guideline project, including the Blood Glucose Control Guideline. The guidelines 

are structured to present the recommendations, practice points, evidence statements, 

documentation of search strategies and search yield and a textual account of the evidence 

underpinning each recommendation. 

Final format and implementation 

The contract between the DoHA and the DA Guideline Development Consortium makes 

provision for locating and synthesising the available evidence on the five index areas into 

guideline recommendations and describing the objective justification for the 

recommendations. Thus, the contract covers the development of the guidelines up to and 

including endorsement by the NHMRC but does not include implementation of the guidelines. 

However, following endorsement by the NHMRC there will need to be an independent 

process of consultation with potential guideline users to determine the final format of the 

guidelines for wide dissemination to clinicians and consumers. Once this format has been 

agreed, an implementation strategy to encourage and facilitate the widespread uptake of the 

guidelines in everyday practice will need to be developed and actioned at national and state 

Type 2 Diabetes Guidelines 1 

Overview, May 2009

and territory level. It is our understanding that the DoHA has developed an implementation 

plan and strategies and is currently obtaining internal sign-off on these before enacting them. 


Overview, May 2009

1.0 Introduction and Overview 

1.1 Diabetes as a health burden 

Results of the national diabetes prevalence survey, AusDiab (Dunstan et al, 2002), which was 

conducted on representative sample of some 11,000 people across Australia, found a 

prevalence of diabetes of 7.4% in people aged 25 years or older. Another 16.4% of the study 

population had either impaired glucose tolerance or impaired fasting glucose. AusDiab also 

confirmed that there is one person with undiagnosed diabetes for every person with diagnosed 

diabetes. Findings from the second phase of AusDiab, a 5-year follow-up survey of people 

who participated in the baseline study, have indicated that every year eight out of every 1,000 

people in Australia developed diabetes (Barry et al, 2006). This, together with the increasing 

number of new cases of pre-diabetes, obesity, the metabolic syndrome, and kidney disease, 

has demonstrated that abnormal glucose metabolism is exerting a major impact on the health 

of Australians (Magliano et al, 2008). 

Diabetes has a demonstrably high health and cost burden (Colagiuri et al, 2003; AIHW, 2008) 

resulting from its long term complications which include: 

- heart disease and stroke 

- foot ulceration, gangrene and lower limb amputation 

- kidney failure 

- visual impairment up to and including blindness 

- erectile dysfunction 

The health burden of diabetes is described in more detail throughout the guideline series but 

to put these complications in perspective, it is worth noting here that, in Australia, diabetes is 

the most common cause of: 

- blindness in people under the age of 60 years 

- end stage kidney disease 

- non-traumatic amputation 

Diabetes is heavily implicated in deaths from cardiovascular disease (CVD) but, due to death 

certificate documentation deficiencies; this link is believed to be substantially under reported. 

At a global level, diabetes is predicted to increase dramatically in the next decade or two 

(IDF, 2006). With an ageing and increasingly overweight and physically inactive population, 

and a cultural mix comprising numerous groups known to be at high risk of type 2 diabetes, 

Australia is a prime candidate for realising the projected increases. 

Due to sheer numbers, the major proportion of the total diabetes burden is attributable to type 

2 diabetes which is the most common form of diabetes and accounts for approximately 85% 

of all diabetes in Australia. Type 2 diabetes occurs predominantly in mature adults with the 

prevalence increasing in older age groups. However, in high risk populations such as 

Aboriginal and Torres Strait Islander people it may become manifest much earlier. 

These guidelines focus exclusively on type 2 diabetes in non-pregnant adults. Like type 1 

diabetes, type 2 diabetes is characterised by high blood glucose levels. However, unlike type 1 

diabetes, the key feature of type 2 diabetes is insulin resistance rather than insulin deficiency. 

Consequently, its treatment does not necessarily require insulin and in many people, 

particularly in the initial years following diagnosis, type 2 diabetes can be successfully 


Overview, May 2009

managed with dietary and general lifestyle modification alone or in combination with oral 

anti-diabetic medications. Insulin therapy may be required if and when oral medication 

becomes ineffective in lowering and maintaining the blood glucose within an acceptable 

range. Assiduous attention to the management of elevated blood pressure, lipid problems and 

overweight is also required as these common features of type 2 diabetes markedly increase the 

risk of long term complications. 

1.2 Key components and principles of diabetes care 

Key components of care 

In 1995, the NSW Health Department identified three key components of diabetes care, 

stating that …. ‘there is consensus supported by published literature that diabetes care and 

outcomes can be improved by providing access for all people with diabetes to: 

- information about their condition and self care education 

- ongoing clinical care to provide optimal metabolic control 

- screening for and appropriate treatment of complications’ (Colagiuri R et al, 1995). 

These and the principles of care below were included in the initial suite of guidelines for type 

2 diabetes and remain as valid now as they were then. 

Principles of care 

The particular expression of the universally accepted diabetes care principles set out below 

was abbreviated from those developed by the UK Clinical Advisory Group (CSAG, 1994) and 

later summarised by the NSW Health Expert Panel on Diabetes (New South Wales (NSW) 

Department of Health, 1996) and was further adapted for this project: 

• People with diabetes should have access to timely and ongoing care from a diabetes 

team. This should ideally include a doctor, nurse and dietitian with specific training 

and experience in the management of diabetes. Additional expertise, for example in 

podiatry, social work, behavioural psychology and counselling, should be available as 

required as should referral access to specialist services for the management of 

identified complications 

• People with diabetes are entitled to access to opportunities for information, education 

and skills acquisition to enable them to participate optimally in their diabetes 

management 

• People with diabetes are entitled to access high quality health services regardless of 

their financial status, cultural background, or place of residence 

• For people with diabetes from community groups who may have special needs eg 

people from Aboriginal, Torres Strait Islander or culturally and linguistically diverse 

backgrounds and the elderly, diabetes care should be specifically tailored to 

overcoming access barriers and providing opportunities for optimising diabetes care 

and outcomes 

• Diabetes teams should routinely evaluate the effectiveness of the care they provide 


Overview, May 2009

1.3 Rationale for the Guidelines 

The magnitude of the impact of diabetes on individuals and society in Australia is manifest in 

its status as a National Health Priority Area since 1996 and the current attention directed to it 

by the Council of Australian Governments’ National Reform Agenda which seeks to address 

and avert a greater impact on productivity than already exists as a result of diabetes. 

For tangible and lasting benefits, evidence based information is required which synthesises 

new and existing evidence to guide primary prevention efforts and assist clinicians to identify 

and treat modifiable primary risk factors, accurately diagnose type 2 diabetes, assess 

metabolic control, provide effective routine care, and make appropriate and timely referrals. 

Since the initial suite of NHMRC diabetes guidelines was released there has been a vast 

improvement in both the volume and quality of the evidence about preventing type 2 diabetes 

which is detailed in the Primary Prevention Guideline. Nonetheless, there remain grave 

concerns that the rapidly increasing prevalence of obesity combined with decreasing levels of 

physical activity will continue to impact negatively on the incidence and prevalence of 

diabetes unless addressed as a mater of urgency. Consequently, the Primary Prevention 

Guideline also cites some of the emerging evidence about environmental influences on food 

consumption and physical activity. 

Type 2 diabetes represents a complex interaction of patho-physiological factors and its 

prevention and successful management requires clinicians and public health practitioners to 

maintain a thorough understanding of these interactions especially since there is now 

irrefutable evidence that both the onset of diabetes and the onset of its complications can be 

prevented or significantly delayed. Given the typically long pre-clinical phase of type 2 

diabetes and that half of all people with diabetes are undiagnosed, the Case Detection and 

Diagnosis Guideline is an important component of this suite of guidelines. 

1BIntegral to the successful management of diabetes is self care knowledge and skills, and the 

capacity of the person with diabetes to adapt their lifestyle to optimise their physical and 

psychological well being. The Patient Education Guideline presents evidence addressing these 

issues. 

The care of type 2 diabetes is predominantly carried out by general practitioners, often under 

‘shared care’ arrangements with local Diabetes Centres and/or private endocrinologists. In 

remote Australia, and even in more densely settled rural regions, the population base is 

insufficient to support specialist diabetes teams and the general practitioner may not have 

local access to specialist referral and support. Regardless of geographical factors, standards of 

diabetes clinical care in Australia are known to be variable. The Chronic Kidney Disease 

Guideline sets out diagnostic criteria and therapies for achieving the treatment targets to guide 

the identification, prevention and management of kidney disease in people with diabetes. 

Microvascular complications (retinopathy, nephropathy and neuropathy) and the increased 

risk of macrovascular complications (ischemic heart disease, stroke and peripheral vascular 

disease) are associated with reduced life expectancy and significant morbidity in type 2 

diabetes. Using therapeutic interventions to lower blood glucose and achieve optimal HbA1c 

levels is critical in preventing diabetes complications and improving the quality of life. The 

Blood Glucose Control Guideline examines the evidence and the relationships among these 

issues. 


Overview, May 2009

1.4 Funding source 

The Type 2 Diabetes Guidelines project is funded by the DoHA under a head contract with 

DA as convenor of the Guideline Development Consortium. The development of the 

guidelines is managed in partnership with DA by The Diabetes Unit at the University Sydney 

under the direction of A/Professor Ruth Colagiuri. 

1.5 The Guideline Development Consortium 

The Guideline Development Consortium led by DA comprises organisations representing 

consumers, specialist diabetes practitioners and primary care physicians and includes: 

• The Australian Diabetes Society (ADS) 

• The Australian Diabetes Educators Association (ADEA) 

• The Royal Australian College of General Practitioners (RACGP) 

• The Diabetes Unit – Menzies Centre for Health Policy (formerly, the Australian 

Health Policy Institute), the University of Sydney. 

Additionally there are a number of collaborators: 

• The NSW Centre for Evidence Based Health Care (University of Western Sydney) 

• The Cochrane Renal Review Group (Westmead Children’s Hospital) 

• The Cochrane Consumer Network 

• The Caring for Australians with Renal Impairment Guidelines Group (CARI), 

• Kidney Health Australia. 

1.6 The scope of the Guidelines 

The brief for the Guideline Development Project was to prepare a set of evidence based 

guidelines for type 2 diabetes to NHMRC standard. 

The Type 2 Diabetes Guidelines target public heath practitioners, clinicians (medical, nursing 

and allied health), diabetes educators and consumers and were designed to be appropriate for 

use in a wide variety of practice settings. The guidelines focus on care processes and 

interventions that are primarily undertaken in the non-acute setting ie they do not deal with 

highly technical procedural interventions such as renal dialysis. 

1.7 Use of the Guidelines 

Guidelines are systematically generated statements which are designed to assist health care 

clinicians and consumers to make informed decisions about appropriate treatment in specific 

circumstances (Field MJ & Lohr, 1990). 

Guidelines are not applicable to all people in all circumstances at all times. The 

recommendations contained in these guidelines are a general guide to appropriate practice and 

are based on the best information available at the time of their development. The clinical 

guidelines should be interpreted and applied on an individual basis in the light of the health 

care practitioner’s clinical experience, common sense, and the personal judgments of 

consumers about what is appropriate for, and acceptable to them. 


Overview, May 2009

1.8 Review date 

New information on type 2 diabetes is continually and rapidly becoming available. The 

Project Management Team and Steering Committee recommend that these guidelines are 

reviewed and revised at least every three years after publication. We anticipate this will be 

June 2012. 

1.9 Economic analysis 

Assessment of economic impact i.e., analysing the cost implications of recommendations has 

become a mandatory component of guideline development. 

1.10 Socio-economic impact 

The Expert Advisory Groups for each guideline were encouraged to adopt a framework that is 

recommended by the NHMRC to identify, appraise and collate evidence of the impact of 

socioeconomic position and other markers of interest eg income, education, occupation, 

employment, ethnicity, housing, area of residence, lifestyle, gender. 


Overview, May 2009

2.0 Organisational structure and staffing 

The organisational structure of the Guideline Development Project (Figure 1) comprises: 

• A Steering Committee 

• Project Management Team 

• Expert Advisory Groups 

• Guidelines Assessment Register Consultant 

• Research Officers 

• Research team 

The Steering Committee consists of a representation from each of the Consortium members, 

the Guideline Project Medical Advisor, and the DoHA. Refer to Appendix i for Terms of 

Reference. The Project Steering Committee provides guidance and directions to the project 

and to the DoHA via DA. The main role was to oversee the project progress and timeline. 

Expert Advisory Groups (EAGs) were established for each of the five guideline areas. They 

have a core composition of a consumer, a general practitioner, content experts nominated by 

the Australian Diabetes Society and the Australian Diabetes Educators Association, and other 

representation as appropriate. Consumers on the expert advisory groups were provided by 

Diabetes Australia as being representative of people with type 2 diabetes who are experienced 

in acting as consumer representatives and who had a detailed understanding of issues 

affecting people with diabetes. Terms of Reference of the EAGs is provided in Appendix ii. 

Lists of the individual members of each of the EAGs are provided in each guideline. 

The Project Management Team. The Diabetes Unit, at Menzies Centre for Health Policy 

(formerly, the Australian Health Policy Institute), University of Sydney was subcontracted by 

DA to manage the project on behalf of the Consortium. The Diabetes Unit provides guidance 

on methods, technical support, data management, co-ordinates the input of the EAGs and 

supervises the project staff on a daily basis. The Project Management Team consists of the 

Director of the Diabetes Unit, the CEO of Diabetes Australia and the project’s Medical 

Advisor. 

Guidelines Assessment Register (GAR) consultans. The NHMRC nominated a GAR 

consultant for each guideline (except the Blood Glucose Control guideline) to provide 

guideline developers with support in relation to utilising evidence-based findings and 

applying the NHMRC criteria. Specifically, the GAR consultants provided advice on 

evaluating and documenting the scientific evidence and developing evidence-based 

recommendations based on the scientific literature and NHMRC procedures. 

Research Officers were recruited or seconded from a variety of research and health care 

disciplines and given additional training to conduct the literature searches, and review, grade 

and synthesise the evidence under the supervision of the Senior Research and Project 

Manager, Dr Seham Girgis, the Chairs of the EAGs and the Project Management Team. 

Research Team refers to the Project Director, Senior Project Manager, Research Officers, and the project’s 

Medical Advisor. 

. 


Overview, May 2009

Figure 1: Organisational Structure 

Steering Committee 

Project Management Team 

GAR 

Consultants 

Expert Advisory Groups 

Research Team 

Research Officers 

lines of communication 

lines of responsibility 


Overview, May 2009

3.0 Methods 

3.1 Development of Protocols 

At the beginning of the project, a Methods Manual was developed for the EAGs and project staff. 

The Manual was based on the NHMRC Standards and procedures for externally developed 

guidelines (NHMRC, 2007) and the series of handbooks on the development, implementation and 

evaluation of clinical practice guidelines published by the NHMRC from 2000–03. The NHMRC 

Standards and procedures document (NHMRC, 2007) introduced an extended set of levels of 

evidence and an approach to assessing a body of evidence and grading of recommendations. 

These standards and handbooks have superseded A guide to the development, implementation and 

evaluation of clinical practice guidelines (NHMRC, 1999), which formed the basis of the initial 

suite of NHMRC guidelines for type 2 diabetes. 

The NHMRC has introduced a requirement for guidelines to consider issues related to costeffectiveness 

and socioeconomic impact. Two publications in the NHMRC toolkit for developing 

clinical practice guidelines have been used to address these issues - how to compare the costs and 

benefits: evaluation of the economic evidence (NHMRC, 2001) and using socioeconomic 

evidence in clinical practice guidelines (NHMRC, 2003). 

The Methods Manual developed for the project contains definitions, procedures and protocols, 

descriptions of study type classifications, checklists and examples of steps and methods for 

critical appraisal of the literature. It also includes the revised level of evidence and the minimum 

requirements for formulating NHMRC evidence based guidelines. 

3.2 Guideline Development Process 

From the literature and expert opinion the following steps were identified as central to the process 

of identifying sources of rigorously objective, peer reviewed information and reviewing, grading, 

and synthesising the literature to generate guideline recommendations: 

1. Define specific issues and generate clinically relevant questions to guide the literature 

searches for each guideline topic. 

2. Search the literature systematically using a range of databases and search strategies. 

3. Sort the search yield on the basis of relevance to the topic area and scientific rigour. 

4. Document the search strategy and the search yield. 

5. Critically review, grade and summarise the evidence. 

6. Assess the body of evidence according to the published NHMRC standard and formulate 

guideline statements and recommendation/s in accordance with the evidence. 

7. Formulate the evidence statements and recommendations. 

8. Conduct quality assurance throughout all these steps. 

Type 2 Diabetes Guidelines 10 Overview, May 2009

12BStep 1: 

Defining issues and questions to direct the literature 

searches 

Each EAG was asked to define key issues for the guideline and to generate a set of questions 

focusing on clinically relevant issues to guide the literature searches. These critical clinical issues 

also formed the focus of the guideline recommendations and accompanying evidence statements. 

A generic framework was developed and centred on issues such as: 

• What are the key treatment/management issues for this area? 

• What anthropometric, clinical or behavioural parameters need to be assessed? 

• Should everyone be assessed or are there particular risk factors which warrant selective 

testing or preventative treatment? 

• What assessment techniques should be used? 

• How often should the assessment be done? 

• How should the results be interpreted? 

• What action should follow from the results (if abnormal) e.g., management, further 

investigation, referral? 

• What are the overall costs of using the intervention? (particularly in relation to changes in 

costs if changes to management are recommended) 

• What is the impact of socioeconomic position and other markers of interest e.g., income, 

education, occupation, employment, ethnicity, housing, area of residence, lifestyle, 

gender. 

EAGs were also advised to frame each question using the ‘PICO’ elements as follows: 

Population or Problem; Intervention (for a treatment intervention question), or Indicator or 

exposure (for a prognosis or aetiology or question), or Index test (for a diagnostic accuracy 

question); Comparator; and Outcome. 

The resulting questions developed by each EAG are presented at the beginning of each guideline 

and again in the Search Strategy and Yield Table. 


Step 2: Searching the literature 

NHMRC clinical practice guidelines are required to be based on systematic identification and 

synthesis of the best available scientific evidence (NHMRC, 2007). A number of systematic 

strategies were used in this project to identify and assess scientific information from the 

published literature. The search strategies were designed to reduce bias and ensure that most of 

the relevant data available on type 2 diabetes were included in the present review and were 

similar to those detailed in the Cochrane Collaboration Reviewers Handbook (Higgins JPT et al). 

Several strategies were used to identify potentially relevant studies and reviews from the 

literature such as: 

Electronic Databases 

Searches were carried out using the following databases: 

• Medline 

• Cochrane Library: Databases of Systematic Reviews, DARE, Controlled Trials Register, 

Central, HTA. 

• Additional databases searched where indicated included: 

Embase 

Cinahl 

Psycho Info 

Eric 

Other (where appropriate) such as Internet, Expert sources, Hand searching of reference 

lists at the end of relevant articles. 

Key words 

The key words (MeSH terms and some free text terms) used when searching these electronic 

databases are presented in detail in the Search Strategy and Yield Table at the end of each 

guideline topic. The EAGs limited their searches through a number of methods including: 

- specification of temporal constraints (e.g. 1999-2008 for the updated guideline) 

- language constraints (English only) 

- where there were overwhelming amounts of literature or if there was a large volume of poor 

quality research, some groups imposed limits by experimental design to exclude the less 

rigorous forms of research. 

Details of specific inclusion criteria for the EAG are also presented, together with the key words, 

at the end of each individual guideline. 

Consultation with colleagues 

The EAGs were encouraged to gather relevant information/articles from other experts and 

colleagues. The Project Management Team collated the questions developed by each EAG to 

direct the literature searches and highlight overlapping questions and requested EAGs and 

Research Officers to send any articles identified as applicable to other guideline topics to the 

EAG. 


15B 

Step 3: Sorting the search yield 

Two or more members of each EAG were responsible for sorting through the search results by 

scanning the lists of titles and abstracts generated by the electronic database searches, 

highlighting potentially relevant articles and requesting printed full articles. Full articles were 

retrieved and those which were relevant were assessed for quality. Articles were considered 

relevant if they provided direct or indirect information addressing one or more of the specified 

‘clinical issues’ questions and were applicable to diabetes care or prevention in Australia. 

Sorting according to study design 

Articles with original data were sorted according to study design. Articles with the most rigorous 

experimental designs were reviewed in the first instance. Articles conducted to other study 

designs were included if they added new information not found in the papers of highest levels of 

evidence. Relevant papers were sorted as follows: 

• Meta-analysis, systematic review of randomised controlled trials (interventions) 

• Randomised controlled trials (RCT) 

• Cohort studies 

• Case control studies 

• Case series, pre-post or post studies 

Exclusion criteria 

Articles were not included for review if it was apparent that their relevance to formulating a 

guideline recommendation was non-existent or negligible. Examples of reasons for non review 

included criteria such as: 

• Studies of inappropriate patient population(s) for the question being addressed 

(epidemiology, specific diet) 

• Hypothesis/mechanism/in vitro study/animal studies 

• Genetic studies that are clinically inapplicable 

• Non-systematic reviews which presented the author’s opinion rather than evidence 


16B 

Step 4: Documenting the search strategy and its yield 

The search strategy (terms and limits) and yield were documented and are available for viewing 

in a table at the end of each guideline. In brief, the Search Strategy and Yield Table recorded 

details about the: 

1. Questions being investigated 

2. Electronic databases searched 

3. MeSH terms and key words used to search the database 

4. Methods for limiting the searches 

5. Number of articles identified by each search 

6. Number of articles relevant from that search 

7. Number of relevant articles identified through other search processes 

8. Number of articles obtained for review 

9. Number of relevant articles which were systematic reviews, RCTs or well designed 

population based studies, quasi-experimental and other (these were documented in the tables 

according to the updated NHMRC Evidence Levels I –IV). 

10. Number of articles reviewed 

11. Highest level of evidence found for each question 


Step 5. Critically reviewing, grading and summarising the evidence 

All relevant articles were reviewed and critically assessed using checklists recommended by the 

NHMRC (2000) (NHMRC, 2000a; NHMRC, 2000b).The NHMRC checklist sets out an explicit 

standardised approach to reviewing and incorporating scientific evidence into clinical practice 

guidelines. 

In addition, Research Officers were asked to construct tables to summarise extraction of data and 

to provide a brief summary of the key results for each article. 

Overall assessment of individual studies 

At the conclusion of reviewing each article, the reviewers rated the evidence in a summary form 

as shown in (Table 1) using the following criteria: 

• Levels of evidence 

The ‘interim’ NHMRC levels of evidence (NHMRC, 2007) was used in this project to 

assess levels of evidence for a range of study designs (Appendix iv). 

• Quality rating 

• Magnitude of effect 

• Relevance rating 

Criteria for quality of evidence, magnitude of effect, and relevance of evidence were based on 

those provided by the NHMRC (2000a &b). These criteria are presented in Appendix iv. 

Table 1: 

Example of an Overall Assessment Report 

Assessment Category 

Level of evidence 

Quality rating 

Magnitude of effect 

Relevance rating 

Rating 

Value Low Medium High 

These assessments were then used in the evidence tables which summarises basic information 

about Each Study reviewed, including an overall assessment of the evidence (Table 2). 

Table 2: 

Author, 

Year 

Author X 

(1999) 

Example of an evidence table with overall study assessment 



Quality Magnitude of Relevance 

Level Study Type Rating Effect Rating Rating 

III-2 Cohort High Low High 


Step 6. Assessing the body of evidence and formulating guideline 

evidence statements and recommendations 

5BIn addition to considerations of the rigour of the research providing the evidence (Tables 1 and 

2), principles for formulating guideline evidence statements and recommendations were derived 

consistent with the NHMRC recommended standard ‘The NHMRC Standards for External 

Developers of Guidelines (NHMRC, 2007). 

For each identified clinical question, evidence statements are based on an assessment of all 

included studies for that question (the Body of Evidence). The NHMRC considers the following 

five components in judging the overall body of evidence (NHMRC, 2007) as specified in the 

‘NHMRC Body of Evidence Matrix’ (Table 3): 

• The evidence base, in terms of the number of studies, level of evidence and quality of 

studies (risk of bias). 

• The consistency of the study results. 

• The potential clinical impact of the proposed recommendation. 

• The generalisability of the body of evidence to the target population for the 

guideline. 

• The applicability of the body of evidence to the Australian healthcare context. 

Based on the body of evidence, recommendation/s was formulated to address each of the 

identified clinical questions for the area. Recommendation/s was written as an action statement. 

6BPrinciples for formulating the guideline recommendation/s 

7BIn the course of the face-to-face meetings of the EAGs, and from published sources, principles 

were identified re-affirming the need for guideline recommendations to: 

• Be developed systematically and objectively by synthesising the best available 

evidence. 

• 8BHave potential to improve health and related outcomes whilst minimising possible 

harms. 

• Be clinically relevant and feasible. 

• Take account of ethical considerations, and acceptability to patients. 

• Centre on interventions which are accessible to those who need them. 

• Propose activities within the scope of the role of those expected to use the guidelines 

e.g., interventions which could be expected to be conducted in routine general 

practice. 

Grading of recommendation/s 

The grading of each recommendation reflects the strength of the recommendation (Table 4) and 

is based on ‘The NHMRC Standards for External Developers of Guidelines (NHMRC, 2007). 

In face-to-face meetings, the EAG, initially graded each of the five components of the NHMRC 

Body of Evidence Matrix (Table 3) for each recommendation and then determined the overall 

grade for the body of evidence by summing the individual component grades (Appendix v). 


Cost effectiveness analyses that were based on modelling, could not be evaluated using the 

NHMRC ‘Body of Evidence Matrix’. Hence, cost-effectiveness recommendations were not 

graded. 


Table 3: 

NHMRC Body of Evidence Matrix 

Component A B C D 

Excellent Good Satisfactory Poor 

Evidence base several level I 

or II studies 

with low risk of 

bias 

one or two level 

II studies with 

low risk of bias 

or a SR/multiple 

Consistency 

all studies 

consistent 

level III studies 


bias 

most studies 

consistent and 

inconsistency 

may be 

explained 

level III studies 


bias, or level I or II 

studies with 

moderate risk of 

bias 

some inconsistency 

reflecting genuine 

uncertainty around 

clinical question 

level IV studies, 

or level I to III 

studies with high 

risk of bias 

evidence is 

inconsistent 

Clinical impact very large substantial moderate slight or restricted 

Generalisability population/s 

studied in body 

of evidence are 

the same as the 

target 

population for 

the guideline 

Applicability 

directly 

applicable to 

Australian 

healthcare 

context 

population/s 

studied in the 

body of evidence 

are similar to the 

target population 

for the guideline 

applicable to 

Australian 

healthcare 

context with few 

caveats 

population/s 

studied in body of 

evidence different 

to target population 

for guideline but it 

is clinically 

sensible to apply 

this evidence to 


probably applicable 

to Australian 

healthcare context 

with some caveats 

population/s 

studied in body of 

evidence different 

to target 

population and 

hard to judge 

whether it is 

sensible to 

generalise to 


not applicable to 

Australian 

healthcare context 


Table 4: 

Definition of NHMRC grades of recommendation 

Grade of 

recommendation 

A 

B 

C 

D 

Description 

Body of evidence can be trusted to guide practice 

Body of evidence can be trusted to guide practice in most 

situations 

Body of evidence provides some support for recommendation(s) 

but care should be taken in its application 

Body of evidence is weak and recommendation must be applied 

with caution 


Step 7. Articulate the guidelines 

For each guideline, clinical questions identified by EAGs are addressed in separate sections in a 

format presenting: 

• Recommendation(s) - including grading. 

• Practice Point (s) – including expert consensus in absence of gradable evidence. 

• Evidence Statements - supporting the recommendations. 

• Background - to issues for the guideline. 

• Evidence - detailing and interpreting the key findings. 

• Evidence tables - summarising the evidence ratings for the articles reviewed. 

At the end of the guideline, references and Search Strategy and Yield Tables documenting 

the identification of the evidence sources were provided. 

To ensure consistency between the guidelines, a template was designed for writers to use when 

drafting the guidelines. 


Step 8. Methods for Quality Assurance across the project 

To ensure optimal accuracy and consistency within and between guideline areas, the Project 

Management Team conducted a range of quality assurance activities throughout the project: 

Quality Assurance, Procedures and Protocols 

• The provision of a Methods Manual which provides written instructions to the Chairs of the 

EAGs and research staff identifying the steps and processes to be followed. 

• The provision to the EAGs of a selection of key published resource material relevant to the 

development of the guidelines (NHMRC tool kit 2000-2003; NHMRC, 2007). 

• Specification and training of research staff on the search process. 

Quality Assurance, Methods 

• The appointment of a Senior Research Officer to the Project Management Team to advise on 

research methods, and provide a resource and support service to the research staff. 

• The establishment of a Methods Advisory Group. 

• The development of questions based on key clinical issues for each guideline topic to focus 

and guide the literature searches and the formulation of the guideline recommendations. As 

previously indicated, these are listed at the beginning of each guideline and the Search 

Strategy and Yield Table at the end of the guideline. 

• The Project Management Team collated and reviewed the questions and undertook a Delphi - 

like process with the Chairs of EAGs to refine these questions. In addition, all EAGs and the 

Project Management Team reviewed the combined questions during one of the three face-toface 

meetings. 

• The design and provision to Chairs of EAGs and Research Officers of standardised forms 

documenting aspects of the search strategy used, the search yield, and the inclusion and 

exclusion of articles for review. A completed Search Strategy and Yield Table follows each 

guideline topic. 

• The Senior Research Officer reviewed: 

− all search terms used to ensure that the searches were comprehensive and that the 

approach was similar across groups. 

− the documentation of the search process. 

• The GAR Consultants worked closely with the Senior Research Officer and EAGs. The 

GAR Consultants provided advice on evaluating and documenting the scientific evidence, 

developing evidence-based recommendations based on the scientific literature, and NHMRC 

procedures. 


• Double culling of the search yield for each guideline topic by project staff and members of 

the EAG. 

• Double reviewing of a sample of completed reviews for each guideline topic by the Senior 

Research Officer or an experienced Research Officer, or by a member of the relevant EAG. 

• Review of the completed recommendations and written description of the literature review for 

each guideline area was undertaken to check for: 

− appropriate use of references 

− accurate application of evidence ratings 

− congruence between the recommendations and evidence statements 

− consistency between recommendations 

− clarity of the literature review findings 


4.0 Consultation Process 

The organisational structure for the Type 2 Diabetes Guidelines Development Project was 

designed to involve and ensure consultation between the Guideline Development Consortium 

(DA, ADS, ADEA, RACGP) and the Diabetes Unit. A number of other strategies were employed 

to ensure wide consultation with a range of stakeholders and interested groups and individuals. 

Initial Consultation 

Prior to commencement of the project, initial consultation included contacting relevant 

professional organisations to discuss the guideline development and to seek nomination of 

content experts. 

Internal Consultation 

The internal communication and interaction between the Project Management Team and the 

research officers included fortnightly meetings, email communications, and regular telephone 

contact. In addition, for each guideline, there was individual informal meetings between the 

research officers and their project managers. 

The Project Steering Committee 

The Project Steering Committee comprised representatives from various organisations (who 

should be consulting with their colleagues in that organisation) include: 

• Diabetes Australia (Mr Matt O’Brien) 

• Medical Advisor (Professor Stephen Colagiuri) 

• Australian Diabetes Society (Dr Maarten Kamp) 

• Australian Diabetes Educators Association (Ms Jane Giles) 

• Royal Australian Collage of General Practice (Professor Mark Harris) 

• Department of Health and Ageing (Ms Suzanne Prosser) 

• The Diabetes Unit, Menzies Centre for Health Policy (Associate Professor Ruth 

Colagiuri) 

During the course of the project, DA convened two face-to-face meetings and three 

teleconferences of the Project Steering Committee members to provide guidance and direction to 

the project. 

Expert Advisory Groups 

The EAGs consulted formally through the inclusion of specific interest groups on the individual 

EAG. Examples include dietitians, clinicians, educators, researches, and consumers. 

Communication strategies with EAG members included: 

• Face-to-face meetings 

− an initial meeting to scope the coverage of the guideline and view the processes 

required to develop it, identify and agree on the roles of the EAG. 

− a final meeting to review and grade the recommendations and body of evidence form. 


• Email communication seeking advice on research questions and search terms and 

requesting review of material developed. 

• Chairs and individual members of EAGs, consulted with additional content experts 

regarding approaches and clinical/content issues as required. 

Consultation with Guidelines Assessment Register (GAR) Consultants. 

The GAR consultant for each guideline provided guideline developers with support in relation to 

utilising evidence-based findings and applying the NHMRC criteria. GAR consultants attended 

face-to-face meetings with EAGs. They provided advice on evaluating and documenting the 

scientific evidence and developing evidence-based recommendations based on the scientific 

literature and NHMRC procedures. 

Consultation with Consumers 

Consumer representatives were selected and appointed by Diabetes Australia for each EAG to 

ensure the consideration of people with type 2 diabetes with respect to their acceptability of the 

proposed guideline recommendations. 

Public Consultation 

All guidelines went through a formal public consultation process. This process was as follows: 

• The guidelines were released for public consultation by Diabetes Australia through the 

NHMRC designated public consultation process between August and October 2008. 

• The call for submissions was advertised in the national public press and a front page 

website advertisement was placed on the Diabetes Australia website, which linked to a 

full website advertisement. 

• The NHMRC also advertised the draft guidelines in their ‘bulletin’. 

• Key stakeholder organisations (Appendix vi) were notified directly by email of the 

availability of the guidelines for public review and requested to comment. The emailed 

notice provided a link to the advertisement on the Diabetes Australia website. 

• As a result of public consultation, submissions were received and referred to the 

Project Management Team: 

– six submissions relating to the Primary Prevention Guideline 

– four submissions relating to Case Detection and Diagnosis Guideline 

– two submissions relating to Patient Education 

– two submissions relating to Chronic Kidney Disease 

– five submissions relating to Blood Glucose Control 

– one submission did not relate to any of the guidelines but made comments on the 

overall process of the guideline development which was subsequently referred to 

the Diabetes Australia Guideline Consortium Steering Committee. 


• The issues raised in these submissions were considered and consulted about internally and 

externally by the guideline developers and were reviewed by the Project Management and 

Research Teams, the Medical Advisor, the relevant EAG, and the GAR Consultant. 

• Key issues from the submissions for each guideline were summarised into table form and 

corresponding responses addressing each issue were presented in separate documents 

entitled “Response to Public Consultation on … ” and accompanied the guideline drafts 

presented to independent review by the NHMRC. 

• Changes to the guidelines as a result of public consultation and as a result of independent 

review by the NHMRC were incorporated into the revised final guidelines. 

Informal Consultation 

Further consultation occurred throughout the project with a wide variety of groups and 

individuals in response to particular issues and needs. For example, the Chronic Kidney Disease 

Guideline has been reviewed by the CARI peer reviewers and presented at the Dialysis, 

Nephrology Transplant 2009 Workshop, Lorne Victoria. Comments from the peer reviewers and 

from the workshop have been incorporated into the subsequent revision of the draft guideline. 


References 

Australian Institute of Health and Welfare (AIHW) (2008). Diabetes: Australian Facts 2008. 

Diabetes Series No. 8. Cat. no. CVD 40. AIHW, Canberra, Australia. 

Barry E, Magliano D, Zimmet P, Polkinghorne K, Atkins R, Dunstan D, Maurray S, Shaw J 

(2006). AusDiab 2005. The Australian Diabetes, Obesity and Lifestyle Study. International 

Diabetes Institute, Melbourne, Australia. 

Colagiuri R, Williamson M, Frommer M (1995). Investing to improve the outcomes of diabetes 

care. NSW Department of Health Public Health Bulletin 6:99-102. 

Colagiuri S, Colagiuri R, Conway B, Grainger D, Davy P (2003). DiabCo$ Australia: Assessing 

the burden of type 2 diabetes in Australia, Diabetes Australia, Canberra, Australia. 

CSAG (1994). Standards of clinical care for people with Diabetes: Report of the Clinical 

Standards Advisory Group. HMSO, London, UK. 

Dunstan D, Zimmet P, Welborn T, De Courten M, Cameron A, Sicree R, Dwyer T, Colagiuri S, 

Jolley D, Knuiman M, Atkins R, Shaw J (2002). The rising prevalence of diabetes and impaired 

glucose tolerance: the Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 

25(5):829-834. 

Field MJ & Lohr K, eds (1990). Clinical practice guidelines: directions for a new program. 

Institute of Medicine, National Academy Press, Washington DC, US. 

Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6. 

(updated September 2006). Available at: 

http://www.cochrane.org/resources/handbook/hbook.htm. Accessed: December 2007. 

International Diabetes Federation (IDF), 2006. Diabetes Atlas, third edition, 

1H http://www.eatals.idf.org (accessed 10 August 2008). 

Magliano D, Barr E, Zimmet P, Cameron A, Dunstan D, Colagiuri S, Jolley D, Owen N, Phillips 

P, Tapp R, Welborn T, Shaw J (2008). Glucose indices, health behaviors, and incidence of 

diabetes in Australia: the Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care 

31(2):267-272. 

National Health and Medical Research Council (NHMRC) (1999). A guide to the development, 

implementation and evaluation of clinical practice guidelines. National Health and Medical 

Research Council, Canberra, Australia. 

National Health and Medical Research Council (NHMRC) (2001). How to compare the costs and 

benefits: evaluation of the economic evidence. NHMRC, Canberra, Australia. 


National Health and Medical Research Council (NHMRC) (2000a). How to review the evidence: 

systematic identification and review of the scientific literature. NHMRC, Canberra, Australia. 

National Health and Medical Research Council NHMRC (2000b). How to use the evidence: 

assessment and application of scientific evidence. . NHMRC, Canberra, Australia. 

National Health and Medical Research Council (NHMRC) (2003). Using socioeconomic 

evidence in clinical practice guidelines. NHMRC, Canberra, Australia. 

National Health and Medical Research Council (NHMRC) (2007). NHMRC additional levels of 

evidence and grades for recommendations for developers of guidelines. NHMRC, Canberra, 

Australia. 

National Health and Medical Research Council (NHMRC) (2007). NHMRC standards and 

procedures for externally developed guidelines. NHMRC, Canberra, Australia. 

New South Wales (NSW) Department of Health (1996). Improving diabetes care and outcomes: 

Principles of care and guidelines for the clinical management of diabetes mellitus. New South 

Wales Department of Health, Sydney, Australia. 


APPENDICES 


Appendix i: Terms of Reference of Steering Committee 

Type 2 Diabetes Guidelines Project 

1. Scope 

The Steering Committee is a composite body which provides guidance and direction to the 

project and advice in relation to the project to the Department of Health and Ageing via 

Diabetes Australia. 

2. Function 

The role of the Steering Committee is to oversight and monitors the project progress and 

timelines. 

3. Membership 

The Steering Committee will comprise representatives from the following organisations: 

• Diabetes Australia 

• The Diabetes Unit, Australian Health Policy Institute 

• Australian Diabetes Society 

• Australian Diabetes Educators Association 

• Royal Australian College of General Practitioners 

• Medical Advisor 

• Consumer – person with type 2 diabetes nominated by Diabetes Australia. 

The Department of Health and Ageing (the Department) will be represented in an advisory role. 

The final composition of the Steering Committee, the operating procedures and the Chair of the 

Committee will be agreed by the Department. 

If a representative is unable to attend a meeting/teleconference they may nominate a proxy 

representative from their own organisation. 

4. Quorum and Voting 

The quorum for Steering Committee meetings is to be 50% of membership plus one additional 

member. 

The Steering Committee shall always attempt to achieve consensus. In the event of decisions 

requiring a vote, each member of the Committee shall exercise a single vote. Decisions will be by 

a majority and the Chair shall have a casting vote. 

5. Communication 

The Steering Committee will communicate directly with Diabetes Australia who in turn will 

liaise with the Department. Communication between the Steering Group and other teams and 

groups is essential and will be facilitated by the Chair of the Committee. 


Frequency of Meetings 

The Steering Committee will meet on at least five occasions throughout the contract period. 

These meetings will comprise two face-to-face meetings and three teleconferences, 

throughout the contract period. 

6. Executive and Operational Support 

The Steering Group Secretariat will be provided by Diabetes Australia. The Secretariat will 

provide support in writing minutes and co-ordinating meetings 

7. Funding 

The costs of travel, accommodation, meeting location (or teleconference) expenses and other 

activities proposed by the Steering Committee will be agreed and borne by Diabetes 

Australia. 


Appendix ii: Terms of Reference for Expert Advisory Groups 

Type 2 Diabetes Guidelines Project 

Purpose 

The Expert Advisory Groups (EAGs) for the National Evidence Based Guidelines for Type 2 

Diabetes are convened by The Diabetes Unit, Menzies Centre for Health Policy (formerly 

Australian Health Policy Institute), The University of Sydney under the head agreement between 

Diabetes Australia and the Department of Health and Ageing to support the development of the 

guidelines by providing: 

1. Overall technical and content advice and critical comment 

2. Input into the development or revision of research questions to guide the literature reviews 

3. Guidance on search terms and for the literature review 

4. Review of drafts of the guidelines and recommendations at critical points along the 

continuum of their development 

5. Perspectives on the feasibility and applicability of the guidelines from the perspective of their 

own disciplines and their peers and colleagues 

Duration 

The EAGs are convened for the duration of the project. It is anticipated this will cover 

approximately 18 months up to end 2008. 

Frequency of Meetings 

It is anticipated that there will be three meetings of the EAGs mainly by teleconference with 

one face-to-face meeting at commencement. 

The EAG members may also be asked to comment on emailed information from time to time. 

Expenses 

Reasonable expenses for travel to meeting will be reimbursed on presentation of original receipts 

Conflict of Interests 

EAG members are asked to declare any/all perceived conflict/s of interest 


Appendix iii: NHMRC Evidence Hierarchy, designations of ‘levels of evidence’ according to type of research question 

Level Intervention Diagnostic accuracy Prognosis Aetiology Screening Intervention 

I A systematic review of level II A systematic review of level A systematic review of level A systematic review of level A systematic review of level II 

Studies 

II studies 

II studies 

II studies 

studies 

II A randomised controlled trial A study of test accuracy A prospective cohort study A prospective cohort study A randomised controlled trial 

with: an independent, 

blinded comparison with a 

valid reference standard, 

among consecutive persons 

with a defined clinical 

presentation 

III-1 A pseudorandomised controlled trial 

(i.e. alternate allocation or some 

other method) 

III-2 

III-3 

IV 

A comparative study with 

concurrent controls: 

▪ Non-randomised, 

experimental trial 

▪ Cohort study 

▪ Case-control study 

▪ Interrupted time series with a 

control group 

A comparative study without 


▪ Historical control study 

▪ Two or more single arm 

study 

▪ Interrupted time series without a 

parallel control group 

Case series with either post-test 

or pre-test/post-test outcomes 

(Source: NHMRC 2007) 

A study of test accuracy 

with: an independent, 

blinded comparison with a 

valid reference standard, 

among non-consecutive 

persons with a defined 

clinical presentation 

A comparison with reference 

standard that does not meet 

the criteria required for 

Level II and III-1 evidence 

Diagnostic case-control 

study 

Study of diagnostic 

yield (no reference 

standard) 

All or none All or none A pseudorandomised 

controlled trial 

(i.e. alternate allocation or 

some other method) 

Analysis of prognostic 

factors amongst persons in 

a single arm of a 

randomised controlled trial 

A retrospective cohort study A comparative study with 


▪ Non-randomised, 

experimental trial 

▪ Cohort study 

▪ Case-control study 

A retrospective cohort study A case-control study A comparative study without 


▪ Historical control study 

▪ Two or more single arm 

study 

Case series, or cohort study of 

persons at different stages of 

disease 

A cross-sectional study or 

case series 

Case series 


Overview, May 2009

Appendix iv: Study Assessment Criteria 

I. Study quality criteria 

Systematic reviews 

1. Were the questions and methods clearly stated? 

2. Is the search procedure sufficiently rigorous to identify all relevant studies? 

3. Does the review include all the potential benefits and harms of the intervention? 

4. Does the review only include randomised controlled trials? 

5. Was the methodological quality of primary studies assessed? 

6. Are the data summarised to give a point estimate of effect and confidence intervals? 

7. Were differences in individual study results adequately explained? 

8. Is there an examination of which study population characteristics (disease subtypes, 

age/sex groups) determine the magnitude of effect of the intervention? 

9. Were the reviewers' conclusions supported by data cited? 

10. Were sources of heterogeneity explored? 

Randomised controlled trials 

1. Were the setting and study subjects clearly described? 

2. Is the method of allocation to intervention and control groups/sites independent of 

the decision to enter the individual or group in the study ? 

3. Was allocation to study groups adequately concealed from subjects, investigators 

and recruiters including blind assessment of outcome? 

4. Are outcomes measured in a standard, valid and reliable way? 

5. Are outcomes measured in the same way for both intervention and control groups? 

6. Were all clinically relevant outcomes reported? 

7. Are factors other than the intervention e.g. confounding factors, comparable between 

intervention and control groups and if not comparable, are they adjusted for in the 

analysis? 

8. Were >80% of subjects who entered the study accounted for at its conclusion?% 

9. Is the analysis by intention to intervene (treat)? 

10. Were both statistical and clinical significance considered? 

11. Are results homogeneous between sites? (Multi-centre/multi-site studies only). 

Cohort studies 

1. Are study participants well-defined in terms of time, place and person? 

2. What percentage (%) of individuals or clusters refused to participate? 

3. Are outcomes measured in a standard, valid and reliable way? 

4. Are outcomes measured in the same way for both intervention and control groups? 

5. Was outcome assessment blind to exposure status? 

6. Are confounding factors, comparable between the groups and if not comparable, are 

they adjusted for in the analysis? 

7. Were >80% of subjects entered accounted for in results and clinical status 

described? 

8. Was follow-up long enough for the outcome to occur 

9. Was follow-up complete and were there exclusions from the analysis? 

10. Are results homogeneous between sites? (Multicentre/multisite studies only). 

Case-control studies 

1. Was the definition of cases adequate? 


Overview, May 2009

2. Were the controls randomly selected from the source of population of the cases? 

3. Were the non-response rates and reasons for non-response the same in both groups? 

4. Is possible that over-matching has occurred in that cases and controls were matched 

on factors related to exposure? 

5. Was ascertainment of exposure to the factor of interest blinded to case/control 

status? 

6. Is exposure to the factor of interest measured in the same way for both case and 

control groups in a standard, valid and reliable way (avoidance of recall bias)? 

7. Are outcomes measured in a standard, valid and reliable way for both case and 

control groups? 

8. Are the two groups comparable on demographic characteristics and important 

potential confounders? and if not comparable, are they adjusted for in the analysis? 

9. Were all selected subjects included in the analysis? 

10. Was the appropriate statistical analysis used (matched or unmatched)? 

11. Are results homogeneous between sites? (Multicentre/multisite studies only). 

Diagnostic accuracy studies 

1. Has selection bias been minimised 

2. Were patients selected consecutively? 

3. Was follow-up for final outcomes adequate? 

4. Is the decision to perform the reference standard independent of the test results (ie 

avoidance of verification bias)? 

5. If not, what per cent were not verified? 

6. Has measurement bias been minimised? 

7. Was there a valid reference standard? 

8. Are the test and reference standards measured independently (ie blind to each other) 

9. Are tests measured independently of other clinical and test information? 

10. If tests are being compared, have they been assessed independently (blind to each 

other) in the same patients or done in randomly allocated patients? 

11. Has confounding been avoided? 

12. If the reference standard is a later event that the test aims to predict, is any 

intervention decision blind to the test result? 

(Sources: adapted from NHMRC1999, NHMRC 2000a, NHMRC 2000b, Liddle et al 96; Khan et 2001) 

Study quality – Rating 

The following was used to rate the quality of each study against the study type criteria listed 

above. 

High: 

Medium: 

Low: 

all or all but one of the criteria were met 

2 or 3 of the criteria were not met 

4 or more of the criteria were not met 


Overview, May 2009

II. Classifying magnitude of the effect 

Ranking Statistical significance Clinical importance of 

benefit 

High Difference is statistically 

significant 

AND There is a clinically 

important benefit for the full 

range of estimates defined by 

Medium 

Difference is statistically 

significant 

AND 

the confidence interval. 

The point estimate of effect 

is clinically important 

BUT the confidence interval 

includes some clinically 

unimportant effects 

Low 

Difference is statistically 

significant| 

OR 

Difference is not statistically 

significant (no effect) or shows 

a harmful effect 

(Source: adapted from the NHMRC classification (NHMRC 2000b) 

AND 

AND 

The confidence interval does 

not include any clinically 

important effects 

The range of estimates 

defined by the confidence 

interval includes clinically 

important effects. 

III. Classifying the relevance of the evidence 

Ranking 

High 

Medium 

Relevance of the evidence 

Evidence of an effect on patient-relevant clinical outcomes, including 

benefits and harms, and quality of life and survival 

Or 

Evidence of an effect on a surrogate outcome that has been shown to be 

predictive of patient-relevant outcomes for the same intervention 

Evidence of an effect on proven surrogate outcomes but for a different 

intervention 

Or 

Evidence of an effect on proven surrogate outcomes but for a different 

intervention and population 

Low 

Evidence confined to unproven surrogate outcomes. 

(Source: adapted from the NHMRC classification (NHMRC 2000b) 


Overview, May 2009

Appendix v: NHMRC Evidence Statement Form 

Key question(s): 


A 

B 

C 

D 



one or two Level II studies with low risk of bias or SR/multiple Level III studies with low risk of bias 




A 

B 

C 

D 





3. Clinical impact (Indicate in the space below if the study results varied according to some 

unknown factor (not simply study quality or sample size) and thus the clinical impact of the intervention could not be determined) 



NA 

A 

B 

C 

D 

A 

B 

C 

D 

A 

B 

C 

D 


Very large 

Moderate 

Slight 

Restricted 













Component 

1. Evidence base 

2. Consistency 

3. Clinical impact 




Rating Description 



possible. 







YES 

NO 


YES 

NO 


YES 

NO 


YES 

NO 


Appendix vi: Key stakeholder organisations notified of public consultation 

• Diabetes Australia State and Territory member organisations including: 

− Australian Diabetes Society 

− Australian Diabetes Educators Association 

• University Schools of Nursing, Medicine, Podiatry, Nutriton/ Dietetics 

• Australian Podiatry Association 

• Australian Podiatry Council 

• Eyes on Diabetes 

• Cooperative Centre for Aboriginal Health 

• Australian Centre for Diabetes Strategies 

• Public and private Diabetes Centres throughout Australia (for which we were able to obtain 

email addresses) 

• State and Federal health departments

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